EP1747204B1 - Tri-substituted ureas as cytokine inhibitors - Google Patents

Tri-substituted ureas as cytokine inhibitors Download PDF

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Publication number
EP1747204B1
EP1747204B1 EP05740166A EP05740166A EP1747204B1 EP 1747204 B1 EP1747204 B1 EP 1747204B1 EP 05740166 A EP05740166 A EP 05740166A EP 05740166 A EP05740166 A EP 05740166A EP 1747204 B1 EP1747204 B1 EP 1747204B1
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Prior art keywords
methyl
methoxy
ethylamino
urea
phenyl
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French (fr)
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EP1747204A1 (en
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Todd Andrew Brugel
Jennifer Anne Townes
Michael Philip Clark
Mark Sabat
Adam Golebiowski
Biswanath De
Stephen Matthew Berberich
Gregory Kent Bosch
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Procter and Gamble Co
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Procter and Gamble Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 1-( N -substituted aryl)-1- N -(2-substituted pyrimidin-4-yl)-3- N -(alkyl or substituted alkyl) ureas which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states.
  • the present invention further relates to compositions comprising said N -1,1,3-tri-substituted ureas.
  • Interleukin -1 IL-1
  • Tumor Necrosis Factor- ⁇ TNF- ⁇
  • cytokines are among the important biological substances known collectively as “cytokines.” These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.
  • pro-inflammatory cytokines are suggested as important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBD), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, psoriasis, and therefore are responsible for the progression and manifestation of human disease states.
  • IBD inflammatory bowel disease
  • the present invention meets the aforementioned needs in that it has been surprisingly found that certain 1-( N -substituted aryl)-1- N -(2-substituted pyrimidin-4-yl)-3- N -(alkyl or substituted alkyl) ureas are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF- ⁇ ) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.
  • IL-1 interleukin-1
  • TNF- ⁇ tumor necrosis factor
  • the first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula: wherein R is substituted or unsubstituted C 1 -C 10 linear or branched alkyl; R 1 has the formula: R 3 is a unit selected from the group consisting of:
  • compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention comprise:
  • the pharmaceutical compositions are directed to one or more diseases related to inflammatory cytokine release, among others, are those chosen from osteoarthritis, rheumatoid arthritis, diabetes, human immunodeficiency virus (HTV) infection, pain (analgesia providing compositions), psoriasis, and inflammatory bowel disease (IBD).
  • diseases related to inflammatory cytokine release are those chosen from osteoarthritis, rheumatoid arthritis, diabetes, human immunodeficiency virus (HTV) infection, pain (analgesia providing compositions), psoriasis, and inflammatory bowel disease (IBD).
  • the present invention further relates to the use of the tri-substituted ureas in the manufacture of medicaments for controlling one or more diseases in humans or higher mammals chosen from osteoarthritis, rheumatoid arthritis, pain (analgesia providing compositions), psoriasis, and inflammatory bowel disease (IBD).
  • diseases in humans or higher mammals chosen from osteoarthritis, rheumatoid arthritis, pain (analgesia providing compositions), psoriasis, and inflammatory bowel disease (IBD).
  • the present invention also provides methods for preparing the 1,1,3-trisubstituted ureas (analogs) of the present invention.
  • the present invention addresses several unmet medical needs, inter alia;
  • the present invention relates to 1,1,3-tri-substituted ureas, for example, 1-(3-substituted aryl)-1-(2-substituted-pyrimidin-4-yl)-3-alkyl ureas, 1-(2-substituted aryl)-1-(2-substituted-pyrimidin-4-yl)-3-alkyl ureas, 1-(2,6-disubstituted substituted aryl)-1-(2-substituted-pyrimidin-4-yl)-3-alkyl ureas, and the like which are suitable for mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause, or manifestation of a wide variety of diseases, disease states, or syndromes.
  • cytokines especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause, or manifestation of a wide variety
  • hydrocarbyl stands for any carbon atom-based unit, said units optionally containing one or more organic functional groups, including inorganic atom comprising salts, inter alia, carboxylate salts, and quaternary ammonium salts.
  • hydrocarbyl is the terms "acyclic” and "cyclic” units which divide hydrocarbyl units into cyclic and non-cyclic classes.
  • Cyclic hydrocarbyl units include monocyclic, bicyclic, fused ring, and spirocyclic ring systems.
  • Heterocyclic and heteroaryl units comprise one or more heteroatoms chosen from nitrogen, oxygen, sulfur, and combinations of these heteroatoms.
  • the substituted and unsubstituted C 1 -C 10 cyclic hydrocarbyl units of the present invention can be bonded directly to the core pyrimidinyl-urea scaffold: or they can be bonded to the core scaffold by way of a linking unit (tethered units) described herein below.
  • Linked or tethered units include alkylenearyl units which are aryl units bonded to the core scaffold by way of an alkylene unit, for example, benzyl units having the formula: or alkyleneheteroaryl units for example a 2-picolyl unit having the formula: wherein R a represents one or more optional substitutions for the aryl ring hydrogen atoms.
  • Non-limiting examples of substituted and unsubstituted C 6 -C 10 alkylenearyl units include 2-methylbenzyl (C 6 ), 3- N,N dimethylaminobenzyl (C 6 ), 4-fluorobenzyl (C 6 ), (8-hydroxy)naphthalen-2-ylmethyl (C 10 ), and 2-(3-hydroxy-phenyl)ethyl (C 6 ).
  • Non-limiting examples of substituted and unsubstituted C 1 -C 10 alkyleneheteroaryl units include piperidin-1-ylmethyl, piperidin-4-ylmethyl, tetrahydro-pyran-4-ylmethyl, morpholin-4-ylmethyl, isoquinolin-1-ylmethyl, and imidazolin-2-ylethyl.
  • Non-limiting examples of C 3 -C 10 alkylenecarbocyclic units include, cyclopropylmethyl (C 3 ), cyclopentylethyl (C 5 ), and cyclohexylmethyl (C 6 ).
  • aryloyl as it relates to the present invention are derivatives of aryl units bonded to a carbonyl unit, aryl units include benzene and naphthalene.
  • a non-limiting example of an aryloyl unit is a substituted or unsubstituted benzoyl unit having the general formula: wherein R a represents one or more possible substitutions for a hydrogen atom.
  • Heteroaryloyl units are units which are derived from heteroaryl units bonded to a carbonyl unit.
  • fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family of the heteroatom containing ring.
  • 1,2,3,4-tetrahydroquinoline having the formula: is, for the purposes of the present invention, considered a heterocyclic unit.
  • 6,7-Dihydro-5 H -[1]pyrindine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • the aryl ring will predominate and determine the type of category to which the ring is assigned.
  • 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • substituted is used throughout the specification.
  • substituted is defined herein as "a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.
  • the units, which substituted for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.”
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • Three hydrogen replacement includes cyano, and the like.
  • substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced.
  • 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring"
  • (N,N-dimethyl-5-amino)octanyl is a " substituted C 8 alkyl unit
  • 3-guanidinopropyl is a "substituted C 3 alkyl unit”
  • 2-carboxypyridinyl is a "substituted heteroaryl unit.”
  • the compounds of the present invention are 1,1,3-tri-substituted ureas having the core scaffold: which comprises a first position nitrogen atom (N 1 ) and a third position nitrogen atom (N 3 ) on either side of a central carbonyl unit.
  • the core scaffold which comprises a first position nitrogen atom (N 1 ) and a third position nitrogen atom (N 3 ) on either side of a central carbonyl unit.
  • a 2-substituted pyrimidin-4-yl unit bearing the R 2 units as the number 2 ring position substituent.
  • R 1 unit as defined herein below.
  • Attached to the third position nitrogen atom (N 3 ) is an R unit which is a unit as described herein below.
  • R units are substituted or unsubstituted C 1 -C 10 linear or branched alkyl.
  • the first aspect of R relates to C 1 -C 4 alkyl units chosen from methyl, ethyl, n-propyl, iso -propyl, n-butyl, sec -butyl, iso- butyl, and tert -butyl.
  • the second aspect of R relates to substituted C 1 -C 4 alkyl units chosen from -CH 2 OH, -CH 2 OCH 3 , -CH 2 CN, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OH, -CHOH(CH 3 ) 2 , -CH 2 CH 2 CH 2 OCH 3 , -CH 2 NH 2 , and -CH 2 N(CH 3 ) 2 .
  • R isocyanates having a protecting group for any reactive heteroatom.
  • an isocyanate having a protecting group present such as OCNCH 2 CH 2 OBoc or OCNCH 2 CH 2 OCbz may be required.
  • the third aspect of R relates to C 5 -C 10 linear or methyl branched alkyl units chosen from n-pentyl, iso -pentyl , neo -pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2-methylheptyl, n-octyl, n-nonyl, and n-decyl.
  • R 1 units have the formula: wherein R 3 is chosen from:
  • the first aspect of R 3 relates to substituted or unsubstituted C 6 aryl units, the first iteration of which relates to units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 4-methylsulfanylphenyl, and 4-dimethylaminophenyl.
  • the second aspect of R 3 relates to substituted or unsubstituted C 3 , C 4 or C 5 heterocyclic units, the first iteration of which relates to substituted and unsubstituted 6-member rings chosen from piperazine, piperidine, morpholine, and tetrahydropyran.
  • the second iteration of this aspect of R 5 relates to 5-member rings chosen from tetrahydrofuran, pyrrolidine, and imidazolidine.
  • the C 3 , C 4 or C 5 heterocyclic units can be bonded to the core structure by any ring atom, for example, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, imidazolidine-5-yl, piperazine-1-yl, piperazine-2-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholin-4-yl, and tetrahydropyran-4-yl.
  • ring atom for example, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, imi
  • R 2 has the formula: the index y is equal to 0 or 1
  • R 4 is a unit selected from the group consisting of:
  • the first Category of R 2 relates to units which are units having an amino linking unit NH-, said R 2 units having the formula:
  • the first aspect of R 4 as it relates to the first category of R 2 includes substituted or unsubstituted C 1 -C 10 linear or branched hydrocarbyl, the first iteration of which includes alkyl units chosen from 1( S )-2-hydroxy-1,2-dimethylpropyl, 1( S )-2-methoxy-1-methylethyl, 1( S )- sec -butyl, and iso-propyl.
  • the second aspect of R 4 relates to substituted or unsubstituted tethered C 6 aryl, the first iteration of which is substituted and unsubstituted phenyl and benzyl (when R 4 comprises a tethered cyclic hydrocarbyl).
  • R 2 units include benzyl and (1 S )-phenylethyl when L 1 is NH-.
  • the third aspect of R 4 as it relates to the first category of R 2 includes C 1 -C 10 substituted or unsubstituted heterocycles, the first iteration of which is a substituted or unsubstituted C 4 or C 5 heterocyclic unit chosen from piperidin-1-yl, piperidin-4-yl, tetrahydropyran-4-yl, and morpholin-4-yl.
  • the second iteration of this aspect relates to substituted or unsubstituted C 4 or C 5 heterocyclic unit tethered to the amino linking unit, -NH-, by way of a methylene unit, -CH 2 -; non-limiting examples of this iteration are chosen from piperidin-1-ylmethyl, piperidin-4-ylmethyl, tetrahydropyran-4-ylmethyl, and morpholin-4-ylmethyl.
  • L and L 1 are linking groups each of which are independently selected from the group consisting of:
  • R 5 is hydrogen, C 1 -C 4 alkyl; or two R 5 units can be taken together to form a carbonyl unit, and the indices x or y are 0 or 1. When x or y is equal to 0 the linking group is absent, when x or y is equal to 1 the linking group is present.
  • the first aspect of L 1 relates to compounds wherein L 1 is chosen from -C(O)-, -CH 2 - or NH-.
  • a first iteration of this aspect of L 1 relates to Category I - first aspect; first, second, and third iterations wherein -NH- is used to link R 4 units which are substituted or unsubstituted C 1 -C 10 linear or branched hydrocarbyl units with the core 1,1,3-tri-substituted urea scaffold.
  • R 4 units includes a unit chosen from 1( S )-2-hydroxy-1,2-dimethylpropyl, 1( S )-2-methoxy-1-methylethyl, 1( S )- sec -butyl, and isopropyl thereby providing an R 2 chosen from a unit chosen from 1( S )-2-hydroxy-1,2-dimethylpropylamino, 1( S )-2-methoxy-1-methylethylamino, 1( S )- sec -butylamino, and isopropylamino.
  • a second aspect of L 1 relates to -NH- units used to link heterocyclic and heterocyclic units tethered with a methylene unit, non-limiting examples of which include piperidin-1-yl, piperidin-1-ylmethyl, piperidin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, morpholin-4-yl, and morpholin-4-ylmethyl.
  • analogs (compounds) of the present invention are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein.
  • the arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
  • the compounds which comprise Category I of the present invention are N-(aryl or substituted aryl)-(2-substituted-pyrimidin-4-yl)-N'-alkyl-ureas having the formula: the first aspect of which relates to R units which are unsubstituted C 1 -C 4 linear or branched alkyl.
  • R 1 and R 2 are defined herein below in Table I. TABLE I No.
  • R R 1 R 2 1 -CH 3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino 2 -CH 3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino 3 -CH 3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino 4 -CH 3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino 5 -CH 3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino 6 -CH 3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino 7 -CH 3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino 8 -CH 3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino 9 -CH 3 4-methylphenyl 2-methoxy-1-methyl-ethylamino 10 -CH 3 4-methylsulfanylphenyl 2-
  • the reaction solution is diluted with EtOAc (4.5 L) and washed with water (3 x 2 L).
  • the combined aqueous layers are extracted with EtOAc (3 L).
  • the combined organic layers are dried over MgSO 4 and filtered.
  • the filter cake is washed with acetone (2 x 1 L) then with 5% MeOH/acetone (2 x 500 mL).
  • the filtrate is concentrated until a thick slurry is obtained. (ca. 1 L volume), hexane (3.5 L) is added and the solution cooled to about 4 °C for 16 hours.
  • the plug is eluted with 4 L of each of the following solutions of acetone/EtOAc: 1:19, 1:9, 1:4, 1:1, and 100% acetone. Any fractions containing relatively pure final product are combined. Thin layer chromatograph (TLC) (5%acetone/EtOAc, 0.1%NH 4 OH) is used to determine which fractions are enhanced in the final product. The combined fractions are concentrated in vacuo to produce a foamy material which is dissolved in Et 2 O (650 mL) and stirred at room temperature. After 1 hour the precipitate which forms can be filtered off. The filtrate is treated with a solution of oxalic acid (89.5 g) in acetone (650 mL) over several minutes.
  • TLC Thin layer chromatograph
  • the solution is cooled to about 5 °C in an ice bath and bistrimethylsilyl trifluoroacetamide (445 g, 1.73 mol) is then carefully added in 100 g aliquots.
  • the addition of the silyl compound is accompanied by a slight warming of the solution to about 10 °C.
  • the ice bath is removed once the addition is completed and the reaction allowed to stir and warm to room temperature over about 1.5 hours.
  • Ethyl isocyanate (594 mL, 7.52 mol) is then added and the reaction is warmed to 50 °C for about 18 hours. Once the reaction is complete, the solution is treated with toluene (500 mL) and concentrated.
  • the concentrate is cooled to 5 °C then taken up in MeOH (2.5 L) which produces an initial exotherm and then water (100 mL).
  • the solution is stirred at room temperature for 1 hour after which the solvent can be removed to afford a crude oily product which is re-dissolved in CH 2 Cl 2 (1.5L) and stirred for an additional hour.
  • the insoluble material which forms is removed by filtration and the filtrate re-concentrated to a clear oil which is passed through a magnesol plug (3.7 Kg) eluting with CH 2 Cl 2 (8 L), 5%, 10%, and 20% acetone/ CH 2 Cl 2 , collecting 4 L fractions.
  • the compounds which comprise the second aspect of Category I of the present invention are N-(aryl or substituted aryl)-(2-substituted-pyrimidin-4-yl)-N'-substituted alkyl-ureas having the formula: wherein R units are substituted C 1 -C 4 linear or branched alkyl.
  • R 1 and R 2 are defined herein below in Table II TABLE II No.
  • R R 1 R 2 101 -CH 2 OH 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino 102 -CH 2 OH 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino 103 -CH 2 OH 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino 104 -CH 2 OH 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino 105 -CH 2 OH 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino 106 -CH 2 OH 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino 107 -CH 2 OH 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino 108 -CH 2 OH 4-fluorophenyl 2-methoxy-1-methyl-ethylamino 109 -CH 2 OH 4-methylphenyl 2-methoxy
  • the present invention also relates to a process for preparing the compounds of the present invention.
  • Aspect 1 of the present invention includes the following steps reagents and procedures.
  • Aspect 1 is outlined herein below in Scheme II and relates to the conversion of III into product I by way of activated intermediate II.
  • 2,4-diaminopyrimidines having the general formula: wherein R 1 and R 4 are defined and detailed herein below, were non-reactive or slow to react with isocyanates. It was surprisingly discovered that treatment of the 2,4-diaminopyrimidine with bistrimethylsilyl trifluoroacetamide thereby forming an activated 2,4-diaminopyrimidine, provided for higher yields and shorter reactions times when the activated 2,4-diaminppyrimidine was treated with an isocyanate.
  • Step (b) of this aspect of the present invention encompassed reacting the activated 2,4-diaminopyrimidine which was formed in situ in step (a) with an isocyanate to form the final tri-substituted urea.
  • Aspect 2 of the present invention includes the following steps reagents and procedures.
  • Aspect 2 is outlined herein below in Scheme III and relates to the conversion of IV into product I by way of salt IIIa and activated intermediate II.
  • Step (b) of Aspect 2 relates to treating said 2,4-diaminopyrimidine with an acid to form the 2,4-diamino-pyrimidine salt. It has been surprisingly discovered that treating the 2,4-diaminopyrimidine intermediate formed in Step (a) of this aspect with oxalic acid affords increased yields of isolated product and ease of purification.
  • Step (c) and Step (d) of Aspect 2 of the present invention relate to reacting said 2,4-diaminopyrimidine salt formed in step (b) with bistrimethylsilyl trifluoroacetamide as described herein above to form in situ an activated 2,4-diaminopyrimidine, followed by reacting said activated 2,4-diaminopyrimidine, formed in situ in step (c), with an isocyanate to form the final product, a tri-substituted urea.
  • Aspect 3 of the present invention includes the following steps reagents and procedures.
  • Aspect 3 is outlined herein below in Scheme IV and relates to the conversion of 2,4-dichloropyrimidine into product I by way of IV, III, salt IIIa and activated intermediate II.
  • step (a) of Aspect 3 leads directly to several process improvements.
  • Na 2 CO 3 is used as a base in step (a) of the present process
  • a large amount of 2,4-di-(substituted or unsubstituted arylamino)pyrimidine is formed.
  • These unwanted by-products are relatively insoluble and are intractable within the reaction matrix.
  • this material changes the reaction matrix. At times a thick slurry forms which on a larger scale is difficult to work with.
  • step (b), step (c) and step (d) of Aspect 3 of the present invention are conducted are the same as described herein above for Aspect 1 and Aspect 2 where they apply.
  • conditions, stoichiometric amounts, and yields are predicated on the reagents used, the intermediates formed, and the desired final compound.
  • the compounds of the present invention are capable of effectively blocking the inflammatory cytokine production from cells, which thereby allows for the mitigation, alleviation, control, abatement, retardation, or prevention of one or more disease states or syndromes which are related to the extracellular release of one or more cytokines.
  • Inflammatory Disease States include those related to:
  • Each of the disease states or conditions which the formulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level.
  • the formulator can determine this amount by any of the known testing procedures known to the artisan.
  • the present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein.
  • One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein.
  • the formulator for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.
  • pro-drug forms of the analogs of the present invention. It may be desirable to formulate the compounds of the present invention as a chemical species which itself is not active against the cytokine activity described herein, but instead are forms of the present analogs which when delivered to the body of a human or higher mammal will undergo a chemical reaction catalyzed by the normal function of the body, inter alia, enzymes present in the stomach, blood serum, said chemical reaction releasing the parent analog.
  • the term "pro-drug” relates to these species which are converted in vivo to the active pharmaceutical.
  • compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention also relates to compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention.
  • compositions of the present invention comprise:
  • excipient and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • compositions according to the present invention include:
  • an effective amount means "an amount of one or more 1,1,3-tri-substituted ureas, effective at dosages and for periods of time necessary to achieve the desired result.”
  • An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated.
  • dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the compositions of the present invention can be administered as frequently as necessary to achieve a therapeutic amount.
  • compositions which provide analgesia comprise:
  • adjunct ingredients which may be combined with the compounds of the present invention: Caffeine, compatible amphetamines, compatible antihistamines, compatible antidepressants.
  • opioid narcotic analgesics may be combined to form pharmaceutical compositions, for example, oxycodone (Percadan, Percacet, Oxycontin, Tylox), pethidine/meperidine (Demerol), methadone (Physeptone, Dolophine), levorphanol (Dromoran, Levodromoran), hydromorphone (Dilaudid), and buprenorphine (Temgesic).
  • excipient and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • compositions or formulations which comprise a precursor or "pro-drug" form of the inflammatory cytokine release-inhibiting compounds according to the present invention.
  • these precursor-comprising compositions of the present invention comprise:
  • the present invention also relates to the use of the 1,1,3-tri-substituted ureas according to the present invention in the manufacture of a medicament for the treatment of inflammatory cytokine related disorders. These disorders are described herein above under Inflammatory Disease States.
  • the inflammatory cytokine inhibitors of the present invention can be delivered in a manner wherein more than one site of control can be achieved, more than one disease state can be modulated at the same time.
  • Elevated levels of pro-inflammatory cytokines are implicated in many disease states and inhibition of pro-inflammatory cytokine production offers the opportunity to treat or prevent a wide range of diseases and conditions involving elevated levels of pro-inflammatory cytokines.
  • Cytokines have been linked to acute and chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, for example, see:
  • An additional aspect of the present invention relates to the use of an effective amount of a 1,1,3-tri-substituted urea according to the present invention in the manufacture of a medicament for the treatment of psoriasis. It is well established that the control of cytokine activity is directly related to the formation of psoriasis and inhibition of this activity can be used as a therapy to control this condition. For example, see:
  • Congestive Heart Failure 1,2,3,4,4 hypertension 5 ; chronic obstructive pulmonary disease and septic shock syndrome 6 ; adult respiratory distress and asthma 6 ; atherosclerosis 9 ; muscle degeneration and periodontal disease 10 ; cachexia, Reiter's syndrome, gout, acute synovitis, eating disorders, inter alia, anorexia and bulimia nervosa 11 ; fever, malaise, myalgia and headaches 12 .
  • the compounds of the present invention can be used in the manufacture of one or more medicaments, examples of which are:
  • the compounds of the present invention can be evaluated for efficacy, for example, measurements of cytokine inhibition constants, K i , and IC 50 values can be obtained by any method chosen by the formulator.
  • Suitable assays include:
  • TNF- ⁇ inhibition can be measured by utilizing lipopolysaccharide (LPS) stimulated human monocytic cells (THP-1) as described in:
  • the inhibition of cytokine production can be observed by measuring inhibition of TNF- ⁇ in lipopolysaccharide stimulated THP-1 cells. All cells and reagents are diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/mL each) and fetal bovine serum (FBS 3%) (GIBCO, all conc. Final). Assay is performed under sterile conditions, only test compound preparation is non-sterile. Initial stock solutions are made in DMSO followed by dilution into RPMI 1640 2-fold higher than the desired final assay concentration.
  • Confluent THP-1 cells (2 x 10 5 cells/mL, final conc.; American Type Culture Company, Rockville, Md.) are added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile) containing 125 ⁇ L test compound (2-fold concentrated) or DMSO vehicle (controls, blanks). DMSO concentration should not exceed 0.2% final. Cell mixture is allowed to preincubate for 15 minutes at 37 °C, 5% CO 2 prior to stimulation with lipopolysaccharide (LPS, 1 ⁇ g/mL final; Sigma L-2630, from E.
  • LPS lipopolysaccharide
  • coli serotype 0111.B4 stored as 1 mg/mL stock in endotoxin screened diluted H 2 O vehicle at -80 °C). Blanks (unstimulated) receive H 2 O vehicle; final incubation volume is 250 ⁇ L. Incubation (4 hours) proceeds as described above. Assay is to be terminated by centrifuging plates 5 minutes at room temperature, 1600 rpm (4033 g); supernatants are then transferred to clean 96 well plates and stored at -80 °C until analyzed for human TNF- ⁇ by a commercially available ELISA kit (Biosource #KHC3015, Camarillo, Ca.). The calculated IC 50 value is the concentration of the test compound that caused a 50% decrease in the maximal TNF- ⁇ production.
  • Arthritis was induced by a single intraarticular injection of iodoacetate into the knee joint of rats anesthetized using (3:1) CO 2 /O 2 .
  • a 10 mg/ml concentration of monosodium iodoacetate (IA) (Aldrich Chemical, Milwaukee, WI) was prepared using injectable saline as the vehicle. After appropriate anesthesia each rat was positioned on its back and the left leg was flexed 90 degrees at the knee. The patellar ligament was palpated below the patella and the injection was made into this region.
  • Each rat received 0.020 ml intra-articular injection of sodium IA, into the left knee using a glass gas tight syringe with a 27 gauge 1/4 inch needle, on day 1 of the study. Care was taken not to advance the needle in too far into the cruciate ligaments.
  • Groups consisted of animals being dosed orally with 1-(4-fluorophenyl)-1- ⁇ 2-[(1 S )-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl ⁇ -3-ethyl-urea (the ( S ) enatiomer of compound 23 from Table I) @ 25 mg/kg BID ( ⁇ every 12 hours for 5 days) and Vehicle dosed orally @ 2.5 ml/kg BID ( ⁇ every 12 hours for 5 days). Following dosing, animals remained on study until humanely sacrificed on day 22 by way of CO2 overdose.
  • the compounds of the present invention have been found to be effective as analgesics.
  • the Rat Thermal Hyperalgesia Model i.e., "Hargreaves Method” [ Hargreaves, K., et al., Pain, (1988), 32:77-88 ], is used to determine the level at which the systemic administration of test compounds attenuate the hyperalgesia response subsequent to an intraplantar injection of carrageenan.
  • Sprague-Dawley male rats weighing 100-150 g and housed two per shoebox cage in sanitary, ventilated animal rooms with controlled temperature, humidity and regular light cycles are used. Rodent chow and water were allowed ad libitum. Animals are acclimated for one week before use. All animal use is in accordance with the United States Department of Agriculture guidelines for humane care.
  • each animal On the first day of study, each animal is acclimated to test equipment and the baseline paw withdrawal latency (PWL) to a radiant heat source is recorded. The following day, animals are orally dosed with vehicle or test compound. Thirty minutes later, each animal receives a 0.1 mL intra plantar injection of carrageenan (1.2% solution, w/v) into the left hind paw. Four hours post-carrageenan injection, animals are returned to the test equipment to determine PWL of the inflamed paw. The animals are then humanely euthanized with an overdose of carbon dioxide. Statistical analysis of data: Change from pre to post PWL for each animal is calculated. Statistical comparison between treatment groups on these two end points are made via an ANCOVA model with treatment terms, as well as pre-treatment measure as baseline covariate.
  • PWL paw withdrawal latency

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Abstract

The present invention relates to 1, 1, 3-tri-substituted ureas having the formula: (I) whrerein R, R1 and R2 are as defined in the claims, which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 1, 1, 3-tri-substituted ureas which inhibit the extracellular release of inflammatory cytokines, and methods for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.

Description

    FIELD OF THE INVENTION
  • The present invention relates to 1-(N-substituted aryl)-1-N-(2-substituted pyrimidin-4-yl)-3-N-(alkyl or substituted alkyl) ureas which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said N-1,1,3-tri-substituted ureas.
    • BACKGROUND OF THE INVENTION
  • Interleukin -1 (IL-1) and Tumor Necrosis Factor-α (TNF-α) are among the important biological substances known collectively as "cytokines." These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.
  • These pro-inflammatory cytokines are suggested as important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBD), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, psoriasis, and therefore are responsible for the progression and manifestation of human disease states.
  • There is therefore a long felt need for compounds and pharmaceutical compositions which comprise compounds, which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them.
  • WO 99/23091 and Lesher et al., J. Med. Chem. 25 (7), pp 837-842, describe substituted ureas having anti-inflammatory and anti-allergic properties, respectively.
    • SUMMARY OF THE INVENTION
  • The present invention meets the aforementioned needs in that it has been surprisingly found that certain 1-(N-substituted aryl)-1-N-(2-substituted pyrimidin-4-yl)-3-N-(alkyl or substituted alkyl) ureas are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF-α) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.
  • The first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula:
    Figure imgb0001
     wherein R is substituted or unsubstituted C1-C10 linear or branched alkyl;
    R1 has the formula:
    Figure imgb0002
     R3 is a unit selected from the group consisting of:
    1. i) substituted or unsubstituted C3-C10 carbocyclic;
    2. ii) substituted or unsubstituted C6-C10 aryl;
    3. iii) substituted or unsubstituted C1-C10 heterocyclic; and
    4. iv) substituted or unsubstituted C1-C10 heteroaryl;
    R2 has the formula:
    Figure imgb0003
     R4 is a unit selected from the group consisting of:
    1. i) hydrogen;
    2. ii) substituted or unsubstituted C1-C10 linear or branched hydrocarbyl;
    3. iii) substituted or unsubstituted C3-C10 carbocyclic;
    4. iv) substituted or unsubstituted C6-C10 aryl;
    5. v) substituted or unsubstituted C1-C10 heterocyclic; and
    6. vi) substituted or unsubstituted C1-C10 heteroaryl;
    L and L1 are linking groups each of which are independently selected from the group consisting of:
    • i) -C(R5)2-;
    • ii) -NR5-; and
    • iii) -O-;
    each R5 is hydrogen, C1-C4 linear or branched alkyl; or two R5 units can be taken together to form a carbonyl unit;
    the indices x and y are each independently 0 or 1, wherein the term 'substituted' has the meaning set out in Claim 1.
  • The present invention further relates to compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, the compositions of the present invention comprise:
    1. a) an amount of one or more 1,1,3-tri-substituted ureas and derivatives thereof according to the present invention which are effective for inhibiting release of inflammatory cytokines; and
    2. b) one or more pharmaceutically acceptable excipients.
  • The pharmaceutical compositions are directed to one or more diseases related to inflammatory cytokine release, among others, are those chosen from osteoarthritis, rheumatoid arthritis, diabetes, human immunodeficiency virus (HTV) infection, pain (analgesia providing compositions), psoriasis, and inflammatory bowel disease (IBD).
  • The present invention further relates to the use of the tri-substituted ureas in the manufacture of medicaments for controlling one or more diseases in humans or higher mammals chosen from osteoarthritis, rheumatoid arthritis, pain (analgesia providing compositions), psoriasis, and inflammatory bowel disease (IBD).
  • The present invention also provides methods for preparing the 1,1,3-trisubstituted ureas (analogs) of the present invention.
  • These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention addresses several unmet medical needs, inter alia;
    1. 1) Providing pharmaceutical compositions capable of effectively blocking inflammatory cytokine production from cells, which thereby allows for the mitigation, alleviation, control, abatement, retardation, or prevention of one or more disease states or syndromes which are related to the extracellular release of one or more cytokines;
      1. a) Affecting the release of Interleukin-1 (IL-1): implicated as the molecule responsible for a large number of disease states, inter alia, rheumatoid arthritis, osteoarthritis, as well as other disease states which relate to connective tissue degradation;
      2. b) Affecting inducible Cycloxygenase-2 (COX-2) expression: inhibitors of cytokine release are proposed as inhibitors of inducible COX-2 expression, which has been shown to be increased by cytokines.
    2. 2) Providing pharmaceutical compositions which are efficacious in affecting the release of Tumor Necrosis Factor-α (TNF-α): This pro-inflammatory cytokine is suggested as an important mediator in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBD), septic shock, cardiopulmonary dysfunction, acute respiratory disease, and cachexia.
    3. 3) Providing a pharmaceutical composition which is efficacious in providing analgesia, or otherwise relieving pain in humans and higher mammals.
  • These and other unmet medical needs are surprisingly resolved by the compounds of the present invention, which are capable of selectively affecting one or more disease states, conditions, or syndromes caused or affected by the extracellular release of cytokines.
  • Although each compound will not be effective against each and every disease state affected by the extracellular release of cytokines, nevertheless, the formulator is left to selecting the compound and make-up of a pharmaceutical composition used to treat the selected condition or illness non-limiting examples of which are described herein below.
  • The present invention relates to 1,1,3-tri-substituted ureas, for example, 1-(3-substituted aryl)-1-(2-substituted-pyrimidin-4-yl)-3-alkyl ureas, 1-(2-substituted aryl)-1-(2-substituted-pyrimidin-4-yl)-3-alkyl ureas, 1-(2,6-disubstituted substituted aryl)-1-(2-substituted-pyrimidin-4-yl)-3-alkyl ureas, and the like which are suitable for mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause, or manifestation of a wide variety of diseases, disease states, or syndromes.
  • The following chemical hierarchy is used throughout the specification to particularly point out and distinctly claim the units which comprise the compounds of the present invention. The term "hydrocarbyl" stands for any carbon atom-based unit, said units optionally containing one or more organic functional groups, including inorganic atom comprising salts, inter alia, carboxylate salts, and quaternary ammonium salts. Encompassed within the term "hydrocarbyl" are the terms "acyclic" and "cyclic" units which divide hydrocarbyl units into cyclic and non-cyclic classes. Cyclic hydrocarbyl units include monocyclic, bicyclic, fused ring, and spirocyclic ring systems. Heterocyclic and heteroaryl units comprise one or more heteroatoms chosen from nitrogen, oxygen, sulfur, and combinations of these heteroatoms.
    1. 1. Substituted and unsubstituted C1-C10 acyclic hydrocarbyl: For the purposes of the present invention the term "substituted and unsubstituted C1-C10 acyclic hydrocarbyl" encompasses 3 categories of units:
      • i) C1-C10 linear or branched alkyl, non-limiting examples of which includes, methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), and tert-butyl (C4); substituted C1-C10 linear or branched alkyl, non-limiting examples of which includes, hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-difluoroethyl (C2), and 3-carboxypropyl (C3).
      • ii) C2-C10 linear or branched alkenyl, non-limiting examples of which includes, ethenyl (C2), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) (C3), and buten-4-yl (C4); substituted C2-C10 linear or branched alkenyl, non-limiting examples of which includes, 2-chloroethenyl (also 2-chlorovinyl) (C2), 4-hydroxybuten-1-yl (C4), 7-hydroxy-7-methyloct-4-en-2-yl (C9), and 7-hydroxy-7-methylocta-3,5-dien-2-yl (C9).
      • iii) C2-C10 linear or branched alkynyl, non-limiting examples of which includes, ethynyl (C2), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), and 2-methyl-hex-4-yn-1-yl (C7); substituted C2-C10 linear or branched alkynyl, non-limiting examples of which includes, 5-hydroxy-5-methylhex-3-ynyl (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), and 5-hydroxy-5-ethylhept-3-ynyl (C9).
    2. 2. Substituted and unsubstituted C1-C10 cyclic hydrocarbyl: For the purposes of the present invention the term "substituted and unsubstituted C1-C10 cyclic hydrocarbyl" encompasses 5 categories of units:
      1. i) C3-C10 carbocyclic units, non-limiting examples of which include, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), decalinyl (C10), and decahydro-azulenyl (C10); substituted C3-C10 carbocyclic units, non-limiting examples of which includes, 2-methylcyclopropyl (C3), 2,5-dimethylcyclopentyl (C5), 4-tert-butylcyclopentyl (C5), 3,5-dichlorocyclohexyl (C6), and 4-hydroxy-cyclohexyl (C6).
      2. ii) C6-C10 aryl units which include, phenyl, naphthen-1-yl, and naphthen-2-yl; substituted C6-C10 aryl units, non-limiting examples of which includes, 4-fluorophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-hydroxyphenyl (C6), 8-hydroxynaphthylen-2-yl (C10), and 6-cyano-naphthylen-1-yl (C10).
      3. iii) C1-C10 heterocyclic units, which are heterocyclic units containing from 1 to 10 carbon atoms and one or more heteroatoms chosen from nitrogen, oxygen, sulfur, and mixtures thereof; non-limiting examples of which include, 1,2,3,4-tetrazolyl (C1), aziridinyl (C2), oxazolyl (C3), tetrahydrofuranyl (C4), dihydropyranyl (C5), piperidin-2-one (valerolactam) (C5), 2,3,4,5-tetrahydro-1H-azepinyl (C6), 2,3-dihydro-1H-indole (C8), and 1,2,3,4-tetrahydro-quinoline (C9); substituted C1-C10 heterocyclic units, non-limiting examples of which include, 2-amino-4,5-dihydro-3H-pyrrolyl (C4), N-methylmorpholinyl (C4), 2,6-dimethylpiperazinyl (C4), and, 1-aza-bicyclo[2.2.2]octane.
      4. iv) C1-C10 heteroaryl units, which are heteroaryl units containing from 1 to 10 carbon atoms and one or more heteroatoms chosen from nitrogen, oxygen, sulfur, and mixtures thereof; non-limiting examples of which include, triazinyl (C3), furanyl (C4), thiophenyl (C4), pyrimidinyl (C4), pyridinyl (C5), and 6,7-dihydro-5H-cyclopenta[b]pyridine (C8); substituted C1-C10 heteroaryl units, non-limiting examples of which include, 4-dimethylaminopyridinyl (C5) and 2-methylindolyl (C8).
  • The substituted and unsubstituted C1-C10 cyclic hydrocarbyl units of the present invention can be bonded directly to the core pyrimidinyl-urea scaffold:
    Figure imgb0004
     or they can be bonded to the core scaffold by way of a linking unit (tethered units) described herein below. Linked or tethered units include alkylenearyl units which are aryl units bonded to the core scaffold by way of an alkylene unit, for example, benzyl units having the formula:
    Figure imgb0005
     or alkyleneheteroaryl units for example a 2-picolyl unit having the formula:
    Figure imgb0006
     wherein Ra represents one or more optional substitutions for the aryl ring hydrogen atoms. Non-limiting examples of substituted and unsubstituted C6-C10 alkylenearyl units include 2-methylbenzyl (C6), 3-N,N dimethylaminobenzyl (C6), 4-fluorobenzyl (C6), (8-hydroxy)naphthalen-2-ylmethyl (C10), and 2-(3-hydroxy-phenyl)ethyl (C6). Non-limiting examples of substituted and unsubstituted C1-C10 alkyleneheteroaryl units include piperidin-1-ylmethyl, piperidin-4-ylmethyl, tetrahydro-pyran-4-ylmethyl, morpholin-4-ylmethyl, isoquinolin-1-ylmethyl, and imidazolin-2-ylethyl. Non-limiting examples of C3-C10 alkylenecarbocyclic units include, cyclopropylmethyl (C3), cyclopentylethyl (C5), and cyclohexylmethyl (C6).
  • The term "aryloyl" as it relates to the present invention are derivatives of aryl units bonded to a carbonyl unit, aryl units include benzene and naphthalene. A non-limiting example of an aryloyl unit is a substituted or unsubstituted benzoyl unit having the general formula:
    Figure imgb0007
     wherein Ra represents one or more possible substitutions for a hydrogen atom. Heteroaryloyl units are units which are derived from heteroaryl units bonded to a carbonyl unit.
  • For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family of the heteroatom containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula:
    Figure imgb0008
     is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro-5H-[1]pyrindine having the formula:
    Figure imgb0009
     is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:
    Figure imgb0010
     is, for the purposes of the present invention, considered a heteroaryl unit.
  • The term "substituted" is used throughout the specification. The term "substituted" is defined herein as "a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below. The units, which substituted for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit." For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring", (N,N-dimethyl-5-amino)octanyl is a " substituted C8 alkyl unit, 3-guanidinopropyl is a "substituted C3 alkyl unit," and 2-carboxypyridinyl is a "substituted heteroaryl unit."
  • The following are the units which can substitute for hydrogen atoms on a hydrocarbyl or other unit:
    • i) -OR8;
    • ii) -C(O)R8;
    • iii) -C(O)OR8
    • iv) -C(O)N(R8)2;
    • v) -CN;
    • vi) -N(R8)2;
    • vii) -halogen;
    • viii) -CF3, -CCl3, -CBr3; and
    • ix) -SO2R8
    wherein each R8 is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl; or two R8 units can be taken together to form a ring comprising from 3-7 atoms.
  • The compounds of the present invention are 1,1,3-tri-substituted ureas having the core scaffold:
    Figure imgb0011
     which comprises a first position nitrogen atom (N1) and a third position nitrogen atom (N3) on either side of a central carbonyl unit. To this core scaffold is attached at the first position nitrogen atom (N1), a 2-substituted pyrimidin-4-yl unit bearing the R2 units as the number 2 ring position substituent. Also attached to the first position nitrogen atom (N1) is an R1 unit as defined herein below. Attached to the third position nitrogen atom (N3) is an R unit which is a unit as described herein below.
  • R units are substituted or unsubstituted C1-C10 linear or branched alkyl.
  • The first aspect of R relates to C1-C4 alkyl units chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
  • The second aspect of R relates to substituted C1-C4 alkyl units chosen from -CH2OH, -CH2OCH3, -CH2CN, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OH, -CHOH(CH3)2, -CH2CH2CH2OCH3, -CH2NH2, and -CH2N(CH3)2. Then preparing the compounds of the present invention which comprise R units according to the second aspect of R, it may be necessary depending upon the substituent, inter alia, hydroxyl, amino, to prepare isocyanates having a protecting group for any reactive heteroatom. For example, when R is -CH2OH, an isocyanate having a protecting group present such as OCNCH2CH2OBoc or OCNCH2CH2OCbz may be required.
  • The third aspect of R relates to C5-C10 linear or methyl branched alkyl units chosen from n-pentyl, iso-pentyl , neo-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2-methylheptyl, n-octyl, n-nonyl, and n-decyl.
  • R1 units have the formula:
    Figure imgb0012
     wherein R3 is chosen from:
    1. i) substituted or unsubstituted C3-C10 carbocyclic;
    2. ii) substituted or unsubstituted C6-C10 aryl;
    3. iii) substituted or unsubstituted C1-C10 heterocyclic; and
    4. iv) substituted or unsubstituted C1-C10 heteroaryl
    the index x is equal to 0 or 1, R3 is a unit selected from the group consisting of:
  • The first aspect of R3 relates to substituted or unsubstituted C6 aryl units, the first iteration of which relates to units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 4-methylsulfanylphenyl, and 4-dimethylaminophenyl.
  • The second aspect of R3 relates to substituted or unsubstituted C3, C4 or C5 heterocyclic units, the first iteration of which relates to substituted and unsubstituted 6-member rings chosen from piperazine, piperidine, morpholine, and tetrahydropyran. The second iteration of this aspect of R5 relates to 5-member rings chosen from tetrahydrofuran, pyrrolidine, and imidazolidine. The C3, C4 or C5 heterocyclic units can be bonded to the core structure by any ring atom, for example, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, imidazolidine-5-yl, piperazine-1-yl, piperazine-2-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholin-4-yl, and tetrahydropyran-4-yl.
  • R2 has the formula:
    Figure imgb0013
     the index y is equal to 0 or 1, R4 is a unit selected from the group consisting of:
    1. i) hydrogen;
    2. ii) substituted or unsubstituted C1-C10 linear or branched hydrocarbyl;
    3. iii) substituted or unsubstituted C3-C10 carbocyclic;
    4. iv) substituted or unsubstituted C6-C10 aryl;
    5. v) substituted or unsubstituted C1-C10 heterocyclic; and
    6. vi) substituted or unsubstituted C1-C10 heteroaryl.
  • The first Category of R2 relates to units which are units having an amino linking unit NH-, said R2 units having the formula:
    Figure imgb0014
  • The first aspect of R4 as it relates to the first category of R2, includes substituted or unsubstituted C1-C10 linear or branched hydrocarbyl, the first iteration of which includes alkyl units chosen from 1(S)-2-hydroxy-1,2-dimethylpropyl, 1(S)-2-methoxy-1-methylethyl, 1(S)-sec-butyl, and iso-propyl.
  • The second aspect of R4 relates to substituted or unsubstituted tethered C6 aryl, the first iteration of which is substituted and unsubstituted phenyl and benzyl (when R4 comprises a tethered cyclic hydrocarbyl). Non-limiting examples of R2 units include benzyl and (1S)-phenylethyl when L1 is NH-.
  • The third aspect of R4 as it relates to the first category of R2, includes C1-C10 substituted or unsubstituted heterocycles, the first iteration of which is a substituted or unsubstituted C4 or C5 heterocyclic unit chosen from piperidin-1-yl, piperidin-4-yl, tetrahydropyran-4-yl, and morpholin-4-yl. The second iteration of this aspect relates to substituted or unsubstituted C4 or C5 heterocyclic unit tethered to the amino linking unit, -NH-, by way of a methylene unit, -CH2-; non-limiting examples of this iteration are chosen from piperidin-1-ylmethyl, piperidin-4-ylmethyl, tetrahydropyran-4-ylmethyl, and morpholin-4-ylmethyl.
  • L and L1 are linking groups each of which are independently selected from the group consisting of:
    • i) -C(R5)2-;
    • ii) -NR5-; and
    • iii) -O-;
  • R5 is hydrogen, C1-C4 alkyl; or two R5 units can be taken together to form a carbonyl unit, and the indices x or y are 0 or 1. When x or y is equal to 0 the linking group is absent, when x or y is equal to 1 the linking group is present.
  • The first aspect of L1 relates to compounds wherein L1 is chosen from -C(O)-, -CH2- or NH-. A first iteration of this aspect of L1 relates to Category I - first aspect; first, second, and third iterations wherein -NH- is used to link R4 units which are substituted or unsubstituted C1-C10 linear or branched hydrocarbyl units with the core 1,1,3-tri-substituted urea scaffold. One non-limiting example of these R4 units includes a unit chosen from 1(S)-2-hydroxy-1,2-dimethylpropyl, 1(S)-2-methoxy-1-methylethyl, 1(S)-sec-butyl, and isopropyl thereby providing an R2 chosen from a unit chosen from 1(S)-2-hydroxy-1,2-dimethylpropylamino, 1(S)-2-methoxy-1-methylethylamino, 1(S)-sec-butylamino, and isopropylamino.
  • A second aspect of L1 relates to -NH- units used to link heterocyclic and heterocyclic units tethered with a methylene unit, non-limiting examples of which include piperidin-1-yl, piperidin-1-ylmethyl, piperidin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, morpholin-4-yl, and morpholin-4-ylmethyl.
  • The analogs (compounds) of the present invention are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
  • The compounds which comprise Category I of the present invention are N-(aryl or substituted aryl)-(2-substituted-pyrimidin-4-yl)-N'-alkyl-ureas having the formula:
    Figure imgb0015
     the first aspect of which relates to R units which are unsubstituted C1-C4 linear or branched alkyl. Examples of R1 and R2 are defined herein below in Table I. TABLE I
    No. R R1 R2
    1 -CH3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    2 -CH3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    3 -CH3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    4 -CH3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    5 -CH3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    6 -CH3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    7 -CH3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    8 -CH3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    9 -CH3 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    10 -CH3 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    11 -CH3 4-methoxyphenyl 1-phenyl-ethylamino
    12 -CH3 4-ethoxyphenyl 1-phenyl-ethylamino
    13 -CH3 4-fluorophenyl 1-phenyl-ethylamino
    14 -CH3 4-methylphenyl 1-phenyl-ethylamino
    15 -CH3 4-methylsulfanylphenyl 1-phenyl-ethylamino
    16 -CH3 4-methoxyphenyl isopropylamino
    17 -CH3 4-ethoxyphenyl isopropylamino
    18 -CH3 4-fluorophenyl isopropylamino
    19 -CH3 4-methylphenyl isopropylamino
    20 -CH3 4-methylsulfanylphenyl isopropylamino
    21 -CH2CH3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    22 -CH2CH3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    23 -CH2CH3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    24 -CH2CH3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    25 -CH2CH3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    26 -CH2CH3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    27 -CH2CH3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    28 -CH2CH3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    29 -CH2CH3 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    30 -CH2CH3 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    31 -CH2CH3 4-methoxyphenyl 1-phenyl-ethylamino
    32 -CH2CH3 4-ethoxyphenyl 1-phenyl-ethylamino
    33 -CH2CH3 4-fluorophenyl 1-phenyl-ethylamino
    34 -CH2CH3 4-methylphenyl 1-phenyl-ethylamino
    35 -CH2CH3 4-methylsulfanylphenyl 1-phenyl-ethylamino
    36 -CH2CH3 4-methoxyphenyl isopropylamino
    37 -CH2CH3 4-ethoxyphenyl isopropylamino
    38 -CH2CH3 4-fluorophenyl isopropylamino
    39 -CH2CH3 4-methylphenyl isopropylamino
    40 -CH2CH3 4-methylsulfanylphenyl isopropylamino
    41 -CH(CH3)2 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    42 -CH(CH3)2 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    43 -CH(CH3)2 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    44 -CH(CH3)2 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    45 -CH(CH3)2 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    46 -CH(CH3)2 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    47 -CH(CH3)2 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    48 -CH(CH3)2 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    49 -CH(CH3)2 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    50 -CH(CH3)2 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    51 -CH(CH3)2 4-methoxyphenyl 1-phenyl-ethylamino
    52 -CH(CH3)2 4-ethoxyphenyl 1-phenyl-ethylamino
    53 -CH(CH3)2 4-fluorophenyl 1-phenyl-ethylamino
    54 -CH(CH3)2 4-methylphenyl 1-phenyl-ethylamino
    55 -CH(CH3)2 4-methylsulfanylphenyl 1-phenyl-ethylamino
    56 -CH(CH3)2 4-methoxyphenyl isopropylamino
    57 -CH(CH3)2 4-ethoxyphenyl isopropylamino
    58 -CH(CH3)2 4-fluorophenyl isopropylamino
    59 -CH(CH3)2 4-methylphenyl isopropylamino
    60 -CH(CH3)2 4-methylsulfanylphenyl isopropylamino
    61 -(CH2)2CH3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    62 -(CH2)2CH3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    63 -(CH2)2CH3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    64 -(CH2)2CH3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    65 -(CH2)2CH3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylanuno
    66 -(CH2)2CH3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    67 -(CH2)2CH3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    68 -(CH2)2CH3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    69 -(CH2)2CH3 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    70 -(CH2)2CH3 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    71 -(CH2)2CH3 4-methoxyphenyl 1-phenyl-ethylamino
    72 -(CH2)2CH3 4-ethoxyphenyl 1-phenyl-ethylamino
    73 -(CH2)2CH3 4-fluorophenyl 1-phenyl-ethylamino
    74 -(CH2)2CH3 4-methylphenyl 1-phenyl-ethylamino
    75 -(CH2)2CH3 4-methylsulfanylphenyl 1-phenyl-ethylamino
    76 -(CH2)2CH3 4-methoxyphenyl isopropylamino
    77 -(CH2)2CH3 4-ethoxyphenyl isopropylamino
    78 -(CH2)2CH3 4-fluorophenyl isopropylamino
    79 -(CH2)2CH3 4-methylphenyl isopropylamino
    80 -(CH2)2CH3 4-methylsulfanylphenyl isopropylamino
    81 -(CH2)3CH3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    82 -(CH2)3CH3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    83 -(CH2)3CH3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    84 -(CH2)3CH3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    85 -(CH2)3CH3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    86 -(CH2)3CH3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    87 -(CH2)3CH3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    88 -(CH2)3CH3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    89 -(CH2)3CH3 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    90 -(CH2)3CH3 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    91 -(CH2)3CH3 4-methoxyphenyl 1-phenyl-ethylamino
    92 -(CH2)3CH3 4-ethoxyphenyl 1-phenyl-ethylamino
    93 -(CH2)3CH3 4-fluorophenyl 1-phenyl-ethylamino
    94 -(CH2)3CH3 4-methylphenyl 1-phenyl-ethylamino
    95 -(CH2)3CH3 4-methylsulfanylphenyl 1-phenyl-ethylamino
    96 -(CH2)3CH3 4-methoxyphenyl isopropylamino
    97 -(CH2)3CH3 4-ethoxyphenyl isopropylamino
    98 -(CH2)3CH3 4-fluorophenyl isopropylamino
    99 -(CH2)3CH3 4-methylphenyl isopropylamino
    100 -(CH2)3CH3 4-methylsulfanylphenyl isopropylamino
  • The compounds which comprise Category I of the present invention can be prepared by the procedure given in Example 1 below as outlined in Scheme I.
    Figure imgb0016
    • EXAMPLE 1 1-(4-Fluorophenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-ethyl-urea (3)
  • (S)-(2-Hydroxy-1,2-dimethyl-propyl)-carbamic acid tert-butyl ester, which is used in step 2 of the present example and which comprises the R2 unit of the final analog, can be prepared using the method of Konno et. al., Chem. Pharm. Bull. (1997), 45, 185, incorporated herein by reference.
  • Preparation of (2-chloro-pyrimidin-4-yl)-(4-fluoro-phenyl)-amine (2): To a solution of 2,4-dichloropyrimidine (260 g, 1.75 mol) in THF (780 mL) and EtOH (3100 mL) is added NaHCO3 (244 g, 2.91 mol). To the slurry which results is added 4-fluoroaniline (162 g, 1.46 mol) in one portion and the resulting mixture allowed to warm to 65 °C and held at this temperature for 10 hours. The reaction if not completed in a single day can be cooled over night. Re-heating the next day to 70 °C for an additional 10 hours is usually sufficient for completion of the reaction. The reaction solution is diluted with EtOAc (4.5 L) and washed with water (3 x 2 L). The combined aqueous layers are extracted with EtOAc (3 L). The combined organic layers are dried over MgSO4 and filtered. The filter cake is washed with acetone (2 x 1 L) then with 5% MeOH/acetone (2 x 500 mL). The filtrate is concentrated until a thick slurry is obtained. (ca. 1 L volume), hexane (3.5 L) is added and the solution cooled to about 4 °C for 16 hours. The thick slurry is collected by filtration, washed with hexane (2 x 500 mL), and dried (20 mmHg, room temperature) to afford 99.43 g (79.3% yield) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (d, J= 6.0 Hz, 1H), 7.59 (m, 2H), 7.11 (m, 2H), 6.64 (d, J= 6.0 Hz, 1H); MS (ESI) m/z 224 (M+1).
  • Preparation of S-3-[4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-2-methyl-butan-2-ol oxalate salt (2): A solution of (S)-(2-Hydroxy-1,2-dimethyl-propyl)-carbamic acid tert-butyl ester (155.6 g, 766 mmol) in CH2Cl2 (350 mL) is added to a room temperature solution oftrifluoroacetic acid (1350 mL) in CH2Cl2 (1 L) over 10-15 minutes or as fast as the gas evolution will allow. The resulting pale brown solution of the deprotected amine is stirred at room temperature an additional 15 minutes and concentrated to yield an oil which is treated with toluene (500 mL) and re-concentrated twice more before being carried forward. The crude amine (S)-2-hydroxy-1,2-dimethylpropylamine is carefully transferred to a 3 L flask using NMP (320 mL). Diisopropylethyl amine (470 mL) is then added. To this solution is added (2-chloro-pyrimidin-4-yl)-(4-fluoro-phenyl)-amine (111.13 g, 497 mmol) and the reaction is warmed to 130 °C for 18 hours, followed by an additional 18 hours at 135 °C. After cooling to room temperature, the reaction solution is diluted with EtOAc (2.5 L) and washed with water (3 x 1 L). The combined aqueous layers are extracted with EtOAc (1 x 1 L) and this is combined with the other organic layers. The combined organic layers are washed with saturated aqueous NaCl (1 x 1 L) and filtered through a 1.2 Kg plug of SiO2 in a 3 L fritted filter. The plug is eluted with 4 L of each of the following solutions of acetone/EtOAc: 1:19, 1:9, 1:4, 1:1, and 100% acetone. Any fractions containing relatively pure final product are combined. Thin layer chromatograph (TLC) (5%acetone/EtOAc, 0.1%NH4OH) is used to determine which fractions are enhanced in the final product. The combined fractions are concentrated in vacuo to produce a foamy material which is dissolved in Et2O (650 mL) and stirred at room temperature. After 1 hour the precipitate which forms can be filtered off. The filtrate is treated with a solution of oxalic acid (89.5 g) in acetone (650 mL) over several minutes. A tacky solid mass particulates after stirring for approximately 1.5 hour and the solid is collected by filtration to afford 126.7 g (70.8% yield) of the desired product as the oxalate salt as a pale violet solid. 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J= 5.9 Hz, 1H), 7.27 (dd, J= 4.8, 9.0 Hz, 2H), 6.98 (t, J= 9.0 Hz, 2H), 5.87 (d, J= 5.9 Hz, 1H), 4.00 - 3.90 (m, 1H), 1.23 (s, 3H), 1.16 (m, 3H), 1.15 (s, 3H); MS (ESI) m/z 291 (M+1).
  • Preparation of 1-(4-fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-ethyl-urea (3): S-3-[4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-2-methyl-butan-2-ol oxalate salt, 2, (173.1 g, 456 mmol) in dichloroethane (2.7 L) is treated with triethylamine (234 mL, 1.68 mole) at room temperature. Once dissolved, the solution is cooled to about 5 °C in an ice bath and bistrimethylsilyl trifluoroacetamide (445 g, 1.73 mol) is then carefully added in 100 g aliquots. The addition of the silyl compound is accompanied by a slight warming of the solution to about 10 °C. The ice bath is removed once the addition is completed and the reaction allowed to stir and warm to room temperature over about 1.5 hours. Ethyl isocyanate (594 mL, 7.52 mol) is then added and the reaction is warmed to 50 °C for about 18 hours. Once the reaction is complete, the solution is treated with toluene (500 mL) and concentrated. The concentrate is cooled to 5 °C then taken up in MeOH (2.5 L) which produces an initial exotherm and then water (100 mL). The solution is stirred at room temperature for 1 hour after which the solvent can be removed to afford a crude oily product which is re-dissolved in CH2Cl2 (1.5L) and stirred for an additional hour. The insoluble material which forms is removed by filtration and the filtrate re-concentrated to a clear oil which is passed through a magnesol plug (3.7 Kg) eluting with CH2Cl2 (8 L), 5%, 10%, and 20% acetone/ CH2Cl2, collecting 4 L fractions. Upgraded (but not pure) fractions by TLC (60% THF/hexane) are collected, concentrated and crystallized from Et2O to give 78.8 g, 47.9% of white crystals. The mother liquors are purified on SiO2 (eluting with a THF/hexane gradient) by preparative chromatography to give an additional 18.7 g for a total of 97.5 g, 59.2% of >98% pure material as a white crystal. [α]D 25 = +3.5 (c = 0.43, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 9.75 (br s, 1H), 7.88 (d, J = 5.9 Hz, 1H), 7.25 -7.10 (m, 4H), 5.51(d, J= 5.9 Hz, 1H), 3.93 (br s, 1H), 3.49 - 3.40 (m, 2H), 1.34 -1.27 (m, 12H); MS (ESI) m/z 362 (M+1); HRMS mlz calcd for C18H25FN5O2 (MH+) 362.1992, found 362.1987.
  • 1-(4-Methoxy-phenyl)-1- {2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-butyl-urea: 1H NMR (300 MHz, CDCl3) δ 9.93 (m, 1H), 7.87 (d, J= 5.8 Hz, 1H), 7.13 (d, J= 8.8 Hz, 2H), 6.99 (d, J= 8.8 Hz, 2H), 5.51 (d, J= 6.2 Hz, 1H), 5.32 (br s, 1H), 4.22 - 3.98 (m, 1H), 3.86 (s, 3H), 3.48 (br d, J= 4.8 Hz, 1H), 3.43 - 3.32 (m, 1H), 3.41 (s, 3H), 3.21- 3.06 (m, 1H), 1.68 -1.53 (m, 2H), 1.52 -1.36 (m, 2H), 1.31 (d, J= 6.6 Hz, 3H), 0.98 (t, J= 7.3 Hz, 3H); MS (ESI) m/z 388 (M+1).
  • 1-(4-Methoxy-phenyl)-1- {2-[(1S)-2-methoxy-1-methoxy-1-methylethylamino]-pyrimidin-4-yl}-3-ethyl-urea: 1H NMR (300 MHz, CDCl3) δ 9.93 (br d, J= 7.3 Hz, 1H), 8.56 (br s, 1H), 7.63 (d, J= 7.3 Hz, 1H), 7.15 (d, J= 8.8 Hz, 2H), 7.03 (d, J= 8.8 Hz, 2H), 6.04 (d, J = 6.6 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.88 (s, 3H), 3.53 - 3.26 (m, 5H), 3.38 (s, 3H), 1.30 (d, J= 6.6 Hz, 3H), 1.25 (t, J = 7.3 Hz, 3H); MS (ESI) mlz 360 (M+1).
  • 1-(4-Methoxyphenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethylpropylamino]-pyrimidin-4-yl}-3-ethyl-urea: 1H NMR (300 MHz, CDCl3) δ 9.58 (br s, 1H), 7.87 (d, J= 5.9 Hz, 1H), 7.15 (d, J= 9.0 Hz, 2H), 7.01 (d, J= 9.0 Hz, 2H), 5.65 (d, J= 6.0 Hz, 1H), 3.87 (s, 4H), 3.49 - 3.40 (m, 2H), 1.33-1.26 (m, 12H); MS (ESI) m/z 374 (M+1).
  • 1-(4-Ethoxyphenyl)-1-{2-[(1S)-2-methoxy-1-methylethylamino]-pyrimidin-4-yl}-3-ethyl-urea: 1H NMR (300 MHz, CDCl3) δ 9.89 (br s, 1H), 7.88 (d, J= 5.9 Hz, 1H), 7.14 (d, J= 9.0 Hz, 1H), 7.14 (d, J= 8.9 Hz, 2H), 7.00 (d, J= 9.0 Hz, 2H), 5.56 (d, J= 5.9 Hz, 1H), 5.50 (br s, 1H), 4.10 (q, J= 6.9 Hz, 3H), 3.51 (d, J= 4.8 Hz, 2H), 3.44 (s, 5H), 1.47 (t, J = 6.9 Hz, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H); MS (ESI) m/z 374 (M+1).
  • 1-(4-Methyl-sulfanylphenyl)-1-{2-[(1S)-2-methoxy-1-methylethylamino]-pyrimidin-4-yl}-3-ethyl-urea: 1H NMR (300 MHz, CDCl3) δ 9.90 (br s, 1H), 7.87 (d, J= 5.8 Hz, 1H), 7.34 (d, J= 8.4 Hz, 2H), 7.14 (d, J= 8.4 Hz, 2H), 5.49 (d, J= 5.8 Hz, 1H), 5.38 (br s, 1H), 4.10 (br s, 1H), 3.49 - 3.27 (m, 7H), 2.52 (s, 3H), 1.33 - 1.19 (m, 6H); MS (ESI) m/z 376 (M+1).
  • 1-(4-Methoxy-phenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-ethyl-urea: 1H NMR (300 MHz, CDCl3) δ 10.10 (br s, 1H), 7.87 (d, J = 5.9 Hz, 1H), 7.15 (d, J= 9.0 Hz, 2H), 7.00 (d, J= 9.0 Hz, 2H), 5.48 (d, J= 5.9 Hz, 1H), 5.03 (br s, 1H), 4.05 - 3.98 (m, 1H), 3.87 (s, 3H), 3.45 (dq, J= 5.3 Hz, 7.3 Hz, 1H), 1.32 (d, J= 6.6 Hz, 6H), 1.28 (t, J= 7.3 Hz, 3H); MS (ESI) m/z 330 (M+1).
  • 1-(4-Methoxy-phenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-isopropyl-urea: 1H NMR (300 MHz, CDCl3) δ 9.97 (d, J= 7.0 Hz, 1H), 7.86 (d, J= 6.0 Hz, 1H), 7.15 (d, J= 8.8 Hz, 2H), 7.00 (d, J= 8.8 Hz, 2H), 5.46 (d, J= 5.9 Hz, 1H), 5.03 - 4.92 (m, 1H), 4.18 - 3.99 (m, 2H), 3.87 (s, 3H), 1.33 (d, J= 6.4 Hz, 6H), 1.29 (d, J= 6.6 Hz, 6H); MS (ESI) m/z 344 (M+1).
  • Further examples of compounds according to Category I of the present invention include:
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    • 1-(4-Metlloxyphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    • 1-(4-Methoxyphenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-methyl-urea;
    • 1-(4-Methoxyphenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-propyl-urea; 1-(4-Methoxyphenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-iso-propyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-methy-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl} -3-ethyl-urea;
    • 1-(4-M ethoxyphenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl} -3-propyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea;
    • 1-(4-Methoxyphenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    • 1-(4-Fluorophenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-methyl-urea;
    • 1-(4-Fluorophenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-propyl-urea;
    • 1-(4-Fluorophenyl)-1-(2-isopropylamino-pyrimidin-4-yl)-3-iso-propyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylaminol-pyrimidin-4-yl}-3-methy-urea;
    • 1-(4-Fluorophenyl)-1- {2-[(1S)-2-bydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-propyl-urea;
    • 1-(4-Fluorophenyl)-1- {2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea; and
    • 1-(4-Fluorophenyl)-1-{2-[(1S)-1-phenyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea.
  • The compounds which comprise the second aspect of Category I of the present invention are N-(aryl or substituted aryl)-(2-substituted-pyrimidin-4-yl)-N'-substituted alkyl-ureas having the formula:
    Figure imgb0017
     wherein R units are substituted C1-C4 linear or branched alkyl. Examples of R1 and R2 are defined herein below in Table II TABLE II
    No. R R1 R2
    101 -CH2OH 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    102 -CH2OH 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    103 -CH2OH 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    104 -CH2OH 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    105 -CH2OH 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    106 -CH2OH 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    107 -CH2OH 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    108 -CH2OH 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    109 -CH2OH 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    110 -CH2OH 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    111 -CH2OH 4-methoxyphenyl 1-phenyl-ethylamino
    112 -CH2OH 4-ethoxyphenyl 1-phenyl-ethylamino
    113 -CH2OH 4-fluorophenyl 1-phenyl-ethylamino
    114 -CH2OH 4-methylphenyl 1-phenyl-ethylamino
    115 -CH2OH 4-methylsulfanylphenyl 1-phenyl-ethylamino
    116 -CH2OH 4-methoxyphenyl isopropylamino
    117 -CH2OH 4-ethoxyphenyl isopropylamino
    118 -CH2OH 4-fluorophenyl isopropylamino
    119 -CH2OH 4-methylphenyl isopropylamino
    120 -CH2OH 4-methylsulfanylphenyl isopropylamino
    121 -CH2OCH3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    122 -CH2OCH3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    123 -CH2OCH3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    124 -CH2OCH3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    125 -CH2OCH3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    126 -CH2OCH3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    127 -CH2OCH3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    128 -CH2OCH3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    129 -CH2OCH3 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    130 -CH2OCH3 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    131 -CH2OCH3 4-methoxyphenyl 1-phenyl-ethylamino
    132 -CH2OCH3 4-ethoxyphenyl 1-phenyl-ethylamino
    133 -CH2OCH3 4-fluorophenyl 1-phenyl-ethylamino
    134 -CH2OCH3 4-methylphenyl 1-plienyl-ethylamino
    135 -CH2OCH3 4-methylsulfanylphenyl 1-phenyl-ethylamino
    136 -CH2OCH3 4-methoxyphenyl isopropylamino
    137 -CH2OCH3 4-ethoxyphenyl isopropylamino
    138 -CH2OCH3 4-fluorophenyl isopropylamino
    139 -CH2OCH3 4-methylphenyl isopropylamino
    140 -CH2OCH3 4-methylsulfanylphenyl isopropylamino
    141 -CH2CH2OH 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    142 -CH2CH2OH 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    143 -CH2CH2OH 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    144 -CH2CH2OH 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    145 -CH2CH2OH 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    146 -CH2CH2OH 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    147 -CH2CH2OH 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    148 -CH2CH2OH 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    149 -CH2CH2OH 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    150 -CH2CH2OH 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    151 -CH2CH2OH 4-methoxyphenyl 1-phenyl-ethylamino
    152 -CH2CH2OH 4-ethoxyphenyl 1-phenyl-ethylamino
    153 -CH2CH2OH 4-fluorophenyl 1-phenyl-ethylamino
    154 -CH2CH2OH 4-methylphenyl 1-phenyl-ethylamino
    155 -CH2CH2OH 4-methylsulfanylphenyl 1-phenyl-ethylamino
    156 -CH2CH2OH 4-methoxyphenyl isopropylamino
    157 -CH2CH2OH 4-ethoxyphenyl isopropylamino
    158 -CH2CH2OH 4-fluorophenyl isopropylamino
    159 -CH2CH2OH 4-methylphenyl isopropylamino
    160 -CH2CH2OH 4-methylsulfanylphenyl isopropylamino
    161 -(CH2)2OCH3 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    162 -(CH2)2OCH3 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    163 -(CH2)2OCH3 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    164 -(CH2)2OCH3 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    165 -(CH2)2OCH3 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    166 -(CH2)2OCH3 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    167 -(CH2)2OCH3 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    168 -(CH2)2OCH3 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    169 -(CH2)2OCH3 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    170 -(CH2)2OCH3 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    171 -(CH2)2OCH3 4-methoxyphenyl 1-phenyl-ethylamino
    172 -(CH2)2OCH3 4-ethoxyphenyl 1-phenyl-ethylamino
    173 -(CH2)2OCH3 4-fluorophenyl 1-phenyl-ethylamino
    174 -(CH2)2OCH3 4-methylphenyl 1-phenyl-ethylamino
    175 -(CH2)2OCH3 4-methylsulfanylphenyl 1-phenyl-ethylamino
    176 -(CH2)2OCH3 4-methoxyphenyl isopropylamino
    177 -(CH2)2OCH3 4-ethoxyphenyl isopropylamino
    178 -(CH2)2OCH3 4-fluorophenyl isopropylamino
    179 -(CH2)2OCH3 4-methylphenyl isopropylamino
    180 -(CH2)2OCH3 4-methylsulfanylphenyl isopropylamino
    181 -(CH2)3CH2OH 4-methoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    182 -(CH2)3CH2OH 4-ethoxyphenyl 2-hydroxy-1,2-dimethyl-propylamino
    183 -(CH2)3CH2OH 4-fluorophenyl 2-hydroxy-1,2-dimethyl-propylamino
    184 -(CH2)3CH2OH 4-methylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    185 -(CH2)3CH2OH 4-methylsulfanylphenyl 2-hydroxy-1,2-dimethyl-propylamino
    186 -(CH2)3CH2OH 4-methoxyphenyl 2-methoxy-1-methyl-ethylamino
    187 -(CH2)3CH2OH 4-ethoxyphenyl 2-methoxy-1-methyl-ethylamino
    188 -(CH2)3CH2OH 4-fluorophenyl 2-methoxy-1-methyl-ethylamino
    189 -(CH2)3CH2OH 4-methylphenyl 2-methoxy-1-methyl-ethylamino
    190 -(CH2)3CH2OH 4-methylsulfanylphenyl 2-methoxy-1-methyl-ethylamino
    191 -(CH2)3CH2OH 4-methoxyphenyl 1-phenyl-ethylamino
    192 -(CH2)3CH2OH 4-ethoxyphenyl 1-phenyl-ethylamino
    193 -(CH2)3CH2OH 4-fluorophenyl 1-phenyl-ethylamino
    194 -(CH2)3CH2OH 4-methylphenyl 1-phenyl-ethylamino
    195 -(CH2)3CH2OH 4-methylsulfanylphenyl 1-phenyl-ethylamino
    196 -(CH2)3CH2OH 4-methoxyphenyl isopropylamino
    197 -(CH2)3CH2OH 4-ethoxyphenyl isopropylamino
    198 -(CH2)3CH2OH 4-fluorophenyl isopropylamino
    199 -(CH2)3CH2OH 4-methylphenyl isopropylamino
    200 -(CH2)3CH2OH 4-methylsulfanylphenyl isopropylamino
  • The following are examples of compounds which comprise the second aspect of Category I of the present invention.
    1-(4-Methoxy-phenyl)-1-{2(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(2-hydroxyethyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(2-methoxyethyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(3-hydroxypropyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylaraino]-pyrimidin-4-yl}-3-(3-methoxypropyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(4-hydroxybutyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(4-methoxybutyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(2-hydroxyethyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(2-methoxyethyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(3-hydroxypropyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(3-methoxypropyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(4-hydroxybutyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(4-methoxybutyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(2-hydroxyethyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(2-methoxyethyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(3-hydroxypropyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(3-methoxypropyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(4-hydroxybutyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-(4-methoxybutyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(2-hydroxyethyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(2-methoxyethyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(3-hydroxypropyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(3-methoxypropyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(4-hydroxybutyl)-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(4-methoxybutyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(2-hydroxyethyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(2-methoxyethyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl} -3-(3-hydroxypropyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(3-methoxypropyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(4-hydroxybutyl)-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(4-methoxybutyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(2-hydroxyethyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(2-methoxyethyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(3-hydroxypropyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(3-methoxypropyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(4-hydroxybutyl)-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-(4-methoxybutyl)-urea;
    1-(4-Methoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(2-hydroxyethyl)-urea;
    1-(4-Methoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(2-methoxyethyl)-urea;
    1-(4-Methoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(3-hydroxypropyl)-urea;
    1-(4-Methoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(3-methoxypropyl)-urea;
    1-(4-Methoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(4-hydroxybutyl)-urea;
    1-(4-Methoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(4-methoxybutyl)-urea;
    1-(4-Fluoro-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(2-hydroxyethyl)-urea;
    1-(4-Fluoro-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(2-methoxyethyl)-urea;
    1-(4-Fluoro-phenyl)-1-[2-(iso-propylanuno)-pyrimidin-4-yl]-3-(3-hydroxypropyl)-urea;
    1-(4-Fluoro-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(3-methoxypropyl)-urea;
    1-(4-Fluoro-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(4-hydroxybutyl)-urea;
    1-(4-Fluoro-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(4-methoxybutyl)-urea;
    1-(4-Ethoxy-phenyl)-1-[2-(iso-propylamino)-pyrinudin-4-yl]-3-(2-hydroxyethyl)-urea;
    1-(4-Ethoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(2-methoxyethyl)-urea;
    1-(4-Ethoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(3-hydroxypropyl)-urea;
    1-(4-Ethoxy-phenyl)-1-[2-(iso-propylamino)-pyrimdin-4-yl]-3-(3-methoxypropyl)-urea;
    1-(4-Ethoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(4-hydroxybutyl)-urea; and
    1-(4-Ethoxy-phenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-(4-methoxybutyl)-urea.
  • Further Categories according to the present invention relate to compounds wherein R2 is a substituted or unsubstituted C1-C10 heterocyclic amino unit. A example of this Category.
  • 3 -Ethyl-1-(4-fluorophenyl)-1-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-urea: 1H NMR (300 MHz, CDCl3) δ 9.77 (m, 1H), 7.92 (d, J= 5.9 Hz, 1H), 7.22 - 7.15 (m, 4H), 5.53 (d, J= 5.9 Hz, 2H), 5.10 (br s, 1H), 4.05 (m, 2H), 3.94 (m, 1H), 3.55 (dt, J = 11.4, 2.2 Hz, 2H), 3.44 (dq, J= 7.3, 5.5 Hz, 2H), 2.10 - 2.05 (m, 2H), 1.63 (dq, J= 11.0, 4.2 Hz, 2H), 1.29 (t, J= 7.3 Hz, 3H); MS (ESI) m/z 360 (M+1).
    • PROCESS
  • The present invention also relates to a process for preparing the compounds of the present invention.
  • Aspect 1 of the present invention includes the following steps reagents and procedures. Aspect 1 is outlined herein below in Scheme II and relates to the conversion of III into product I by way of activated intermediate II.
    Figure imgb0018
  • Step (a): reacting a 2,4-diaminopyrimidine with an amine activating agent to form in situ an activated 2,4-diamino-pyrimidine. Prior to the present invention it was found that 2,4-diaminopyrimidines having the general formula:
    Figure imgb0019
     wherein R1 and R4 are defined and detailed herein below, were non-reactive or slow to react with isocyanates. It was surprisingly discovered that treatment of the 2,4-diaminopyrimidine with bistrimethylsilyl trifluoroacetamide thereby forming an activated 2,4-diaminopyrimidine, provided for higher yields and shorter reactions times when the activated 2,4-diaminppyrimidine was treated with an isocyanate. In fact, because of the enhanced reactivity of this activated pyrimidine, lower temperatures can be used, thereby allowing for the use of substituted or unsubstituted C1-C10 linear or branched acyclic hydrocarbyl isocyanates. For example, methyl isocyanate, ethyl isocyanate, n-propyl isocyanate, iso-propyl isocyanate, and the like, which typically have low boiling points, could be used to form their corresponding 1-(2-substituted amino-pyrimidin-4-yl)-1-(substituted aryl)-3-(C1-C10 linear or branched alkyl)-ureas utilizing the procedure outlined herein below.
  • Step (b) of this aspect of the present invention encompassed reacting the activated 2,4-diaminopyrimidine which was formed in situ in step (a) with an isocyanate to form the final tri-substituted urea.
  • Aspect 2 of the present invention includes the following steps reagents and procedures. Aspect 2 is outlined herein below in Scheme III and relates to the conversion of IV into product I by way of salt IIIa and activated intermediate II.
    Figure imgb0020
    Figure imgb0021
  • Step (a): reacting a 2-chloro-4-aminopyrimidine with an amine to form a 2,4-diaminopyrimidine.
  • Step (b) of Aspect 2 relates to treating said 2,4-diaminopyrimidine with an acid to form the 2,4-diamino-pyrimidine salt. It has been surprisingly discovered that treating the 2,4-diaminopyrimidine intermediate formed in Step (a) of this aspect with oxalic acid affords increased yields of isolated product and ease of purification.
  • Step (c) and Step (d) of Aspect 2 of the present invention relate to reacting said 2,4-diaminopyrimidine salt formed in step (b) with bistrimethylsilyl trifluoroacetamide as described herein above to form in situ an activated 2,4-diaminopyrimidine, followed by reacting said activated 2,4-diaminopyrimidine, formed in situ in step (c), with an isocyanate to form the final product, a tri-substituted urea.
  • Aspect 3 of the present invention includes the following steps reagents and procedures. Aspect 3 is outlined herein below in Scheme IV and relates to the conversion of 2,4-dichloropyrimidine into product I by way of IV, III, salt IIIa and activated intermediate II.
    Figure imgb0022
    Figure imgb0023
  • Step (a): reacting 2,4-dichloropyrimidine with an amine in the presence of NaHCO3 to form a 2-chloro-4-aminopyrimidine.
  • It was surprisingly discovered during the course of developing the present invention that the availability, purity, and ease of synthesis of the 2,4-diaminopyrimidine starting material, the starting point for Aspect 1 of the present invention, was predicated on the ability to easily and cost effectively prepare sufficient quantities of the 2-chloro-4-aminopyrimidine starting material of Aspect 2. The 2-chloro-4-aminopyrimidines described herein as part of the present invention are not generally commercially available. In addition, this is the point at which the first of the three urea substituents are added to the core pyrimidine scaffold High yield, low cost, ease of preparation are important to this step in order for the process described herein to provide a benefit to the consumer. It is well understood the cost of providing pharmaceuticals reflects the cost of starting materials and the process for preparing and purifying the intermediates and final products.
  • Key to the preparation of the final compounds of the present invention is the surprising discovery that the use of NaHCO3 in step (a) of Aspect 3 leads directly to several process improvements. When Na2CO3 is used as a base in step (a) of the present process, a large amount of 2,4-di-(substituted or unsubstituted arylamino)pyrimidine is formed. These unwanted by-products are relatively insoluble and are intractable within the reaction matrix. Aside from using up a large portion of the starting amine and therefore requiring an adjustment in the reaction stoichiometry, this material changes the reaction matrix. At times a thick slurry forms which on a larger scale is difficult to work with.
  • The conditions under which step (b), step (c) and step (d) of Aspect 3 of the present invention are conducted are the same as described herein above for Aspect 1 and Aspect 2 where they apply. As will be understood by those skilled in the art, conditions, stoichiometric amounts, and yields are predicated on the reagents used, the intermediates formed, and the desired final compound.
  • Compounds listed and described herein above have been found in many instances to exhibit activities (IC50 in the cell based assay described herein below or ones which are referenced herein) at a concentration below 1 micromolar (µM).
  • The compounds of the present invention are capable of effectively blocking the inflammatory cytokine production from cells, which thereby allows for the mitigation, alleviation, control, abatement, retardation, or prevention of one or more disease states or syndromes which are related to the extracellular release of one or more cytokines. Inflammatory Disease States include those related to:
    1. i) Interleukin-1 (IL-1); implicated as the molecule responsible for a large number of disease states, inter alia, rheumatoid arthritis, osteoarthritis, as well as other disease states which relate to connective tissue degradation.
    2. ii) Cycloxygenase-2 (COX-2): inhibitors of cytokine release are proposed as inhibitors of inducible COX-2 expression, which has been shown to be increased by cytokines. M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A., 89, 4888 (1998).
    3. iii) Tumor Necrosis Factor-α (TNF-α): This pro-inflammatory cytokine is suggested as an important mediator in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBD), septic shock, cardiopulmonary dysfunction, acute respiratory disease, and cachexia.
    4. iv) The compounds of the present invention have been found to be surprisingly effective in providing analgesia, or otherwise relieving pain in humans and higher mammals.
  • Each of the disease states or conditions which the formulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the known testing procedures known to the artisan.
  • The present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.
  • Related to this aspect are the various precursor of "pro-drug" forms of the analogs of the present invention. It may be desirable to formulate the compounds of the present invention as a chemical species which itself is not active against the cytokine activity described herein, but instead are forms of the present analogs which when delivered to the body of a human or higher mammal will undergo a chemical reaction catalyzed by the normal function of the body, inter alia, enzymes present in the stomach, blood serum, said chemical reaction releasing the parent analog. The term "pro-drug" relates to these species which are converted in vivo to the active pharmaceutical.
    • FORMULATIONS
  • The present invention also relates to compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, the compositions of the present invention comprise:
    1. a) an effective amount of one or more 1,1,3-tri-substituted ureas and derivatives thereof according to the present invention which are effective for inhibiting release of inflammatory cytokines; and
    2. b) one or more pharmaceutically acceptable excipients.
  • For the purposes of the present invention the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition."
  • The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • Examples of compositions according to the present invention include:
    1. a) from about 0.001 mg to about 1000 mg of one or more 1,1,3-tri-substituted ureas according to the present invention; and
    2. b) one or more excipient.
  • Another embodiment according to the present invention relates to the following compositions:
    1. a) from about 0.01 mg to about 100 mg of one or more 1,1,3-tri-substituted ureas according to the present invention; and
    2. b) one or more pharmaceutical excipient.
  • A further embodiment according to the present invention relates to the following compositions:
    1. a) from about 0.1 mg to about 10 mg of one or more 1,1,3-tri-substituted ureas according to the present invention; and
    2. b) one or more pharmaceutical excipient.
  • The term "effective amount" as used herein means "an amount of one or more 1,1,3-tri-substituted ureas, effective at dosages and for periods of time necessary to achieve the desired result." An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of the present invention can be administered as frequently as necessary to achieve a therapeutic amount.
  • Another aspect of the present invention relates to pharmaceutical compositions which provide analgesia, the compositions of the present invention comprise:
    1. a) an amount of one or more 1,1,3-tri-substituted ureas and derivatives thereof according to the present invention in an amount effective for providing analgesia;
    2. b) one or more pharmaceutically acceptable excipients.
  • As second embodiment of this analgesia-providing aspect of the present invention includes compositions comprising:
    1. a) an amount of one or more 1,1,3-tri-substituted ureas and derivatives thereof according to the present invention in an amount effective for providing analgesia;
    2. b) an effective amount of one or more compounds having pain relief properties; and
    3. c) one or more pharmaceutically acceptable excipients.
  • The following are examples of compounds having pain relief properties or compounds which are effective in providing relief from pain and which can be suitably combined with the compounds of the present invention:
  • Acetaminophen, aspirin, difunisal, dipyrone, ibuprofen, naproxen, fenoprofen, fenbufen, ketoprofen, flurbiprofen, indomethacin, ketorolac, diclofenac, floctafenine, piroxicam, celecoxib, and rofecoxib.
  • The following are examples of adjunct ingredients which may be combined with the compounds of the present invention: Caffeine, compatible amphetamines, compatible antihistamines, compatible antidepressants.
  • In addition, opioid narcotic analgesics may be combined to form pharmaceutical compositions, for example, oxycodone (Percadan, Percacet, Oxycontin, Tylox), pethidine/meperidine (Demerol), methadone (Physeptone, Dolophine), levorphanol (Dromoran, Levodromoran), hydromorphone (Dilaudid), and buprenorphine (Temgesic).
  • For the purposes of the present invention the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition."
  • The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • The present invention also relates to compositions or formulations which comprise a precursor or "pro-drug" form of the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, these precursor-comprising compositions of the present invention comprise:
    1. a) an effective amount of one or more derivatives of the 1,1,3-tri-substituted ureas according to the present invention which act to release in vivo the corresponding analog which is effective for inhibiting release of inflammatory cytokines; and
    2. b) one or more pharmaceutically acceptable excipients.
    METHOD OF USE
  • The present invention also relates to the use of the 1,1,3-tri-substituted ureas according to the present invention in the manufacture of a medicament for the treatment of inflammatory cytokine related disorders. These disorders are described herein above under Inflammatory Disease States.
  • Because the inflammatory cytokine inhibitors of the present invention can be delivered in a manner wherein more than one site of control can be achieved, more than one disease state can be modulated at the same time.
  • Elevated levels of pro-inflammatory cytokines are implicated in many disease states and inhibition of pro-inflammatory cytokine production offers the opportunity to treat or prevent a wide range of diseases and conditions involving elevated levels of pro-inflammatory cytokines. Cytokines have been linked to acute and chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, for example, see:
    • i) Rankin, E. C. C., et al. 1997, British J. Rheum. 35:334;
    • ii) Stack, W. A., et al. 1997, The Lancet 349:521;
  • An additional aspect of the present invention relates to the use of an effective amount of a 1,1,3-tri-substituted urea according to the present invention in the manufacture of a medicament for the treatment of psoriasis. It is well established that the control of cytokine activity is directly related to the formation of psoriasis and inhibition of this activity can be used as a therapy to control this condition. For example, see:
  • Lamotalos J., et al., "Novel Biological Immunotherapies for Psoriasis." Expert Opinion Invstigative Drugs; (2003); 12, 1111-1121.
  • Compositions herein are also effective as a therapy against the following disease states:
  • Congestive Heart Failure1,2,3,4,4; hypertension5; chronic obstructive pulmonary disease and septic shock syndrome6; adult respiratory distress and asthma6; atherosclerosis9; muscle degeneration and periodontal disease10; cachexia, Reiter's syndrome, gout, acute synovitis, eating disorders, inter alia, anorexia and bulimia nervosa11; fever, malaise, myalgia and headaches12.
    1. 1. Han et al., Trends in Cardiovascular Medicine, 10:19, (2000);
    2. 2. Hunter et al., New England Journal of Medicine, 341:1276, (1999);
    3. 3. Behr et al. Circulation, 102:II-289, (2000);
    4. 4. Shimamoto et al, Circulation: 102:II-289, (2000);
    5. 5. Aukrust et al., American Journal of Cardiology,. 83:376 (1999);
    6. 6. Singh, et al., Journal of Hypertension, 9:867 (1996);
    7. 7. Dinarello, C. A., Nutrition 11:492 (1995);
    8. 8. Renzetti, et al. Inflammation Res. 46:S143;
    9. 9. Elhage, et al., Circulation 97:242 (1998);
    10. 10. Howells, Oral Dis. 1:266 (1995);
    11. 11. Holden, et al., Medical Hypothesis 47:423 (1996);
    12. 12. Beisel, American Journal of Clinical Nutrition, 62:813 (1995).
  • The compounds of the present invention can be used in the manufacture of one or more medicaments, examples of which are:
    1. i) a compound for use in the manufacture of a medicament for the treatment of inflammation;
    2. ii) a compound for use in the manufacture of a medicament for the treatment of rheumatoid arthritis or osteoarthritis;
    3. iii) a compound for use in the manufacture of a medicament for the treatment of inflammatory bowel disease (IBD), septic shock, cardiopulmonary dysfunction, acute respiratory disease, and cachexia;
    4. iv) a compound for use in the manufacture of a medicament for the treatment of psoriasis;
    5. v) a compound for use in the manufacture of a medicament for the treatment of pain.
    PROCEDURES
  • The compounds of the present invention can be evaluated for efficacy, for example, measurements of cytokine inhibition constants, Ki, and IC50 values can be obtained by any method chosen by the formulator.
  • Examples of suitable assays include:
    1. i) UV-visible substrate enzyme assay as described by L. A1 Reiter, Int. J. Peptide Protein Res., 43, 87-96 (1994).
    2. ii) Fluorescent substrate enzyme assay as described by Thornberry et al., Nature, 356, 768-774 (1992).
    3. iii) PBMC Cell assay as described in U.S. 6,204,261 B1 Batchelor et al., issued March 20, 2001 .
    Inhibition of Tumor Necrosis Factor, TNF-α
  • In addition, Tumor Necrosis Factor, TNF-α, inhibition can be measured by utilizing lipopolysaccharide (LPS) stimulated human monocytic cells (THP-1) as described in:
    1. i) K. M. Mohler et al., "Protection Against a Lethal Dose of Endotoxin by an Inhibitor of Tumour Necrosis Factor Processing", Nature, 370, pp 218-220 (1994).
    2. ii) U.S. 6,297,381 B1 Cirillo et al., issued October 2, 2001 , incorporated by reference and reproduced herein below in relevant portion thereof.
  • The inhibition of cytokine production can be observed by measuring inhibition of TNF-α in lipopolysaccharide stimulated THP-1 cells. All cells and reagents are diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/mL each) and fetal bovine serum (FBS 3%) (GIBCO, all conc. Final). Assay is performed under sterile conditions, only test compound preparation is non-sterile. Initial stock solutions are made in DMSO followed by dilution into RPMI 1640 2-fold higher than the desired final assay concentration. Confluent THP-1 cells (2 x 105 cells/mL, final conc.; American Type Culture Company, Rockville, Md.) are added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile) containing 125 µL test compound (2-fold concentrated) or DMSO vehicle (controls, blanks). DMSO concentration should not exceed 0.2% final. Cell mixture is allowed to preincubate for 15 minutes at 37 °C, 5% CO2 prior to stimulation with lipopolysaccharide (LPS, 1 µg/mL final; Sigma L-2630, from E. coli serotype 0111.B4; stored as 1 mg/mL stock in endotoxin screened diluted H2O vehicle at -80 °C). Blanks (unstimulated) receive H2O vehicle; final incubation volume is 250 µL. Incubation (4 hours) proceeds as described above. Assay is to be terminated by centrifuging plates 5 minutes at room temperature, 1600 rpm (4033 g); supernatants are then transferred to clean 96 well plates and stored at -80 °C until analyzed for human TNF-α by a commercially available ELISA kit (Biosource #KHC3015, Camarillo, Ca.). The calculated IC50 value is the concentration of the test compound that caused a 50% decrease in the maximal TNF-α production.
  • Results for representative compounds according to the present invention are listed in Table below. TABLE III
    Compound Name TNF-a IC50 (nM)
    1-(4-Methoxyphenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-ethyl-urea 16
    1-(4-Fluorophenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-ethyl-urea 30
    1-(4-Methoxyphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea 666
    1-(4-Ethoxyphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea 276
    1-(4-Methylsulfanylphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea 26
    1-(4-Methoxyphenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-butyl-urea 324
    1-(4-Fluorophenyl)-1-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-3-ethyl-urea 86
    1-(4-Fluorophenyl)-1-[2-(iso-propylamino)-pyrimidin-4-yl]-3-ethyl-urea 28
    • Iodoacetate Induced Arthritis Test.
  • The following procedure is used for in vivo testing for arthritis efficacy. Sprague-Dawley male rats weighting 200-225 grams from Harlan (Oregon, WI) housed singly in wire cages in sanitary, ventilated animal rooms with controlled temperature, humidity and regular light cycles were used. Rodent chow (Ralston-Purina, Richmond, IN) and water were allowed ad libitum. Animals were acclimated for one week before use.
  • Arthritis was induced by a single intraarticular injection of iodoacetate into the knee joint of rats anesthetized using (3:1) CO2/O2. A 10 mg/ml concentration of monosodium iodoacetate (IA) (Aldrich Chemical, Milwaukee, WI) was prepared using injectable saline as the vehicle. After appropriate anesthesia each rat was positioned on its back and the left leg was flexed 90 degrees at the knee. The patellar ligament was palpated below the patella and the injection was made into this region. Each rat received 0.020 ml intra-articular injection of sodium IA, into the left knee using a glass gas tight syringe with a 27 gauge 1/4 inch needle, on day 1 of the study. Care was taken not to advance the needle in too far into the cruciate ligaments.
  • Groups consisted of animals being dosed orally with 1-(4-fluorophenyl)-1-{2-[(1S)-2-hydroxy-1,2-dimethyl-propylamino]-pyrimidin-4-yl}-3-ethyl-urea (the (S) enatiomer of compound 23 from Table I) @ 25 mg/kg BID (~every 12 hours for 5 days) and Vehicle dosed orally @ 2.5 ml/kg BID (~every 12 hours for 5 days). Following dosing, animals remained on study until humanely sacrificed on day 22 by way of CO2 overdose.
  • Animals were weighed weekly during this study for health monitoring. Animals were sacrificed on day 22 and the left joint was immediately disarticulated and fixed in 10% buffered formalin for 24 to 48 hours prior to capturing the image.
  • After fixation, an image of the tibial cartilage surface was captured using an Optimas (Optimas, Media Cybernetics LP, Silver Springs, MA) image analysis system. The image was used for grading the severity of damaged cartilage. Three independent observers assessed the damage in a blinded manner using a scale of 0-4 of increasing severity (0 = normal; 4 = maximum severity).
  • As described herein above, the compounds of the present invention have been found to be effective as analgesics. One convenient means for evaluating pain and for measuring the effective amount of compound(s) necessary to achieve analgesia and, therefore, provide a means for determining the amount of compound(s) which comprises a pharmaceutical composition of the present invention and the amount of compound(s) necessary for use in the methods described herein, is the Rat Thermal Hyperalgesia Model as described herein below.
  • The Rat Thermal Hyperalgesia Model, i.e., "Hargreaves Method" [Hargreaves, K., et al., Pain, (1988), 32:77-88], is used to determine the level at which the systemic administration of test compounds attenuate the hyperalgesia response subsequent to an intraplantar injection of carrageenan.
    • Analgesia Test Method:
  • Sprague-Dawley male rats weighing 100-150 g and housed two per shoebox cage in sanitary, ventilated animal rooms with controlled temperature, humidity and regular light cycles are used. Rodent chow and water were allowed ad libitum. Animals are acclimated for one week before use. All animal use is in accordance with the United States Department of Agriculture guidelines for humane care.
  • On the first day of study, each animal is acclimated to test equipment and the baseline paw withdrawal latency (PWL) to a radiant heat source is recorded. The following day, animals are orally dosed with vehicle or test compound. Thirty minutes later, each animal receives a 0.1 mL intra plantar injection of carrageenan (1.2% solution, w/v) into the left hind paw. Four hours post-carrageenan injection, animals are returned to the test equipment to determine PWL of the inflamed paw. The animals are then humanely euthanized with an overdose of carbon dioxide.
    Statistical analysis of data: Change from pre to post PWL for each animal is calculated. Statistical comparison between treatment groups on these two end points are made via an ANCOVA model with treatment terms, as well as pre-treatment measure as baseline covariate.

Claims (19)

  1. A compound, including all enantiomeric or diasteriomeric forms and pharmaceutically acceptable salts thereof, having the formula:
    Figure imgb0024
     wherein
    R is substituted or unsubstituted C1-C10 linear or branched alkyl;
    R1 has the formula
    Figure imgb0025
     R2 has the formula
    Figure imgb0026
     L and L1 are linking groups, each of which is independently selected from:
    i) -C(R5)2-;
    ii) -NR5-; and
    iii) -O-;
    each R5 is hydrogen, C1-C4 linear or branched alkyl; or two R5 units can be taken together to form a carbonyl unit;
    the indices x and y are each independently 0 or 1;
    R3 is a unit selected from the group consisting of:
    i) substituted or unsubstituted C3-C10 carbocyclic;
    ii) substituted or unsubstituted C6-C10 aryl;
    iii) substituted or unsubstituted C1-C10 heterocyclic; and
    iv) substituted or unsubstituted C1-C10 heteroaryl;
    R4 is a unit selected from the group consisting of:
    i) hydrogen;
    ii) substituted or unsubstituted C1-C10 linear or branched hydrocarbyl;
    iii) substituted or unsubstituted C3-C10 carbocyclic;
    iv) substituted or unsubstituted C6-C10 aryl;
    v) substituted or unsubstituted C1-C10 heterocyclic; and
    vi) substituted or unsubstituted C1-C10 heteroaryl;
    wherein the term 'substituted' means that one or more hydrogen atoms of the hydrocarbyl part of a respective moiety may be replaced by a substituent or several substituents selected from
    i) -OR8;
    ii) -C(O)R8;
    iii) -C(O)OR8
    iv) -C(O)N(R8)2;
    v) -CN;
    vi) -N(R8)2;
    vii) -halogen;
    viii) -CF3, -CCl3, -CBr3; and
    ix) -S02R8;
    wherein each R8 is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl; or two R8 units can be taken together to form a ring comprising from 3-7 atoms, the substituting units being capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time, or replacing two hydrogen atoms on two adjacent carbons to form said substituent.
  2. A compound according to Claim 1 wherein R is a C1-C4 alkyl unit chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
  3. A compound according to Claim 1 wherein R is a substituted C1-C4 alkyl unit chosen from -CH2OH, -CH2OCH3, -CH2CN, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OH, -CHOH(CH3)2, -CH2CH2CH2OCH3, -CH2NH2, and -CH2N(CH3)2.
  4. A compound according to Claim 1 wherein R is a C5-C10 linear or methyl branched alkyl unit.
  5. A compound according to Claim 4 wherein R is chosen from n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2-methylheptyl, n-octyl, n-nonyl, and n-decyl.
  6. A compound according to Claim 1 wherein R3 is chosen from 4-methoxyphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-methylphenyl, and 4-methylsulfanylphenyl.
  7. A compound according to Claim 1 wherein R2 is chosen from (S)-2-hydroxy-1,2-dimethyl-propylaroino, (R)-2-hydroxy-1,2-dimethyl-propylamino, (S)-2-methoxy-1-methyl-ethylamino, (R)-2-methoxy-1-methyl-ethylamino, (S)-1-phenyl-ethylamino, (R)-1-phenyl-ethylamino, and isopropylamino.
  8. A compound according to Claim 1 chosen from:
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-butyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-butyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-sec-butyl-urea;
    1-(4-Methoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-tert-butyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-butyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-butyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-sec-butyl-urea;
    1-(4-Fluoro-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-tert-butyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    1-(4-Ethoxy-pheuyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrhnidin-4-yl}-3-propyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-butyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-butyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-sec-butyl-urea;
    1-(4-Ethoxy-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-tert-butyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-methyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-ethyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-propyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-propyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-butyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-iso-butyl-urea;
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-sec-butyl-urea; and
    1-(4-Methyl-phenyl)-1-{2-[(1S)-2-methoxy-1-methyl-ethylamino]-pyrimidin-4-yl}-3-tert-butyl-urea.
  9. A composition comprising:
    a) one or more compounds according to any of Claims 1 to 8; and
    b) one or more pharmaceutically compatible excipients.
  10. A composition according to Claim 9 additionally comprising one or more further compounds having pain relief properties.
  11. A composition according to Claim 10 wherein the one or more further compounds having pain relief properties are chosen from acetaminophen, aspirin, difunisal, dipyrone, ibuprofen, naproxen, fenoprofen, fenbufen, ketoprofen, flurbiprofen, indomethacin, ketorolac, diclofenac, floctafenine, piroxicam, celecoxib, rofecoxib, oxycodone, pethidine, methadone, levorphanol, hydromorphone, and buprenorphizte.
  12. The use of a compound according to any of Claims 1 to 8 in the manufacture of a medicament for the treatment of inflammation.
  13. The use of a compound according to any of Claims 1 to 8 in the manufacture of a medicament for the treatment of rheumatoid arthritis or osteoarthritis.
  14. The use of a compound according to any of Claims 1 to 8 in the manufacture of a medicament for the treatment of inflammatory bowel disease (IBD), septic shock, cardiopulmonary dysfunction, acute respiratory disease, or cachexia.
  15. The use of a compound according to any of Claims 1 to 8 in the manufacture of a medicament for the treatment of psoriasis.
  16. The use of a compound according to any of Claims 1 to 8 in the manufacture of a medicament for the treatment or relief of pain.
  17. The use according to Claim 16 wherein the medicament further comprises one or more compounds having pain relief properties chosen from acetaminophen, aspirin, difunisal, dipyrone, ibuprofen, naproxen, fenoprofen, fenbufen, ketoprofen, flurbiprofen, indomethacin, ketorolac, diclofenac, floctafenine, piroxicam, celecoxib, rofecoxib, oxycodone, pethidine, methadone, levorphanol, hydromorphone, and buprenorphine.
  18. A process for preparing a tri-substituted urea according to Claim 1 comprising:
    a) reacting a 2,4-diaminopyrimidine having the formula:
    Figure imgb0027
     with bis-trimethylsilyl trifluoroacetamide to form in situ an activated 2,4-diamino-pyrimidine; and
    b) reacting said activated 2,4-diaminopyrimidine, formed in situ in step (a), with an isocyanate having the formula:

            OCN-R

    to form a tri-substituted urea having the formula:
    Figure imgb0028
     wherein:
    R is substituted or unsubstituted C1-C10 linear or branched alkyl;
    R1 has the formula:
    Figure imgb0029
    L is a linking group independently selected from the group consisting of:
    i) -C(R5)2-;
    ii) -NR5-; and
    iii) -O-;
    each R5 is hydrogen, C1-C4 linear or branched alkyl, or two R5 units can be taken together to form a carbonyl unit; and the index x is 0 or 1;
    R3 is a unit selected from the group consisting of:
    i) substituted or unsubstituted C3-C10 carbocyclic;
    ii) substituted or unsubstituted C6-C10 aryl;
    iii) substituted or unsubstituted C1-C10 heterocyclic; and
    iv) substituted or unsubstituted C1-C10 heteroaryl;
    R4 is a unit selected from the group consisting of:
    i) hydrogen;
    ii) substituted or unsubstituted C1-C10 linear or branched hydrocarbyl;
    iii) substituted or unsubstituted C3-C10 carbocyclic;
    iv) substituted or unsubstituted C6-C10 aryl;
    v) substituted or unsubstituted C1-C10 heterocyclic; and
    vi) substituted or unsubstituted C1-C10 heteroaryl;
    wherein the term 'substituted' has the meaning set out in Claim 1.
  19. A process for preparing a tri-substituted urea according to Claim 1, comprising:
    a) reacting 2,4-dichloropyrimidine with an amine having the formula:

            R1-NH2

    in the presence of NaHCO3, wherein R1 is substituted or unsubstituted C6-C10 aryl, to form a 2-chloro-4-aminopyrimidine having the formula:
    Figure imgb0030
    b) reacting said 2-chloro-4-aminopyrimidine with an amine having the formula:

            R4-NH2

    wherein R4 is chosen from:
    i) hydrogen;
    ii) substituted or unsubstituted C1-C10 linear or branched hydrocarbyl;
    iii) substituted or unsubstituted C3-C10 carbocyclic;
    iv) substituted or unsubstituted C6-C10 aryl;
    v) substituted or unsubstituted C1-C10 heterocyclic; and
    vi) substituted or unsubstituted C1-C10 heteroaryl;
    to form a 2,4-diaminopyrimidine having the formula:
    Figure imgb0031
    c) treating said 2,4-diaminopyrimidine with oxalic acid to form the 2,4-diaminopyrimidine oxalic acid salt;
    d) reacting said 2,4-diaminopyrimidine oxalic acid salt with bis-trimethylsityl trifluoroacetamide form an activated 2,4-diaminopyrimidine; and
    e) reacting said activated 2,4-diaminopyrimidine with an isocyanate having the formula:

            OCN-R

    wherein R is substituted or unsubstituted C1-C10 linear or branched alkyl; to form a tri-substituted urea having the formula:
    Figure imgb0032
    wherein the term 'substituted' has the meaning set out in Claim 1.
EP05740166A 2004-04-22 2005-04-20 Tri-substituted ureas as cytokine inhibitors Active EP1747204B1 (en)

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